Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][Cl:3])=[CH:20][CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ccccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: ClCc1ccc(Oc2ccccn2)cc1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 4.4 gram (0.037 mole) of thionyl chloride in 75 mL of dry methylene chloride was cooled to 0° C., and 0.07 gram (catalyst) of pyridine was added. A solution of 5.0 grams (0.025 mole) of (4-(2-pyridyloxy)phenyl)methanol in 25 mL of methylene chloride was then added drop wise. Upon completion addition of addition, the reaction mixture was allowed to warm to 22° C. where it stirred for 30 minutes. After this time an aliquot of the reaction mixture was taken up in ethyl acetate and treated with solid sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The NMR spectrum was consistent with the proposed structure. Inasmuch as this compound is unstable, it was used without further purification. The yield was estimated at about 5.0 grams.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:44][CH2:45][CH2:46][C:47]([CH3:62])([CH3:61])[CH2:48][CH2:49]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C=O)C.O>[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:44][CH2:45][CH2:46][C:47]([CH3:61])([CH3:62])[CH2:48][CH2:49][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: Oc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a stirred solution of 2-(1-trityl-1H-imidazol-4-yl)phenol (1.50 g, 3.73 mmol) in anhydrous DMF (10 mL) was added NaH (4.10 mmol) portion wise at 0° C. The resulting suspension was allowed to stir for 15 min. To the resulting suspension was added a solution of 3,3-dimethylpentane-1,5-diyl bis(4-methylbenzenesulfonate) (3.28 g, 7.45 mmol) in DMF (8 mL) and the mixture was allowed to stir overnight at rt. The reaction mixture was diluted with water (50 mL) and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford a yellow oil which was purified by flash column chromatography on silica gel to afford the desired product (1.60 g, 64% yield). 1H NMR (A): 0.84 (s, 6H), 1.34 (t, 2H, J=7.32 Hz), 1.52 (t, 2H, J=7.20 Hz), 2.38 (s, 3H), 3.85 (t, 2H, J=7.32 Hz), 4.02 (t, 2H, J=7.32 Hz), 6.79 (d, 1H, J=8.19 Hz), 7.03 (t, 1H, J=7.47 Hz, 7.14-7.35 (m, 18H), 7.44 (s, 1H), 7.50 (s, 1H), 7.72-7.77 (m, 2H), 8.23 (d, 1H, J=5.64 Hz). 1H NMR (B): 1.08 (s, 6H), 1.95 (t, 4H, J=7.08 Hz), 4.16 (t, 4H, J=6.96 Hz), 6.92-7.02 (m, 4H), 7.20 (m, 2H), 7.45 (s, 2H), 7.65 (s, 2H), 7.86 (d, 2H, J=6.12 Hz), 8.19 (br s, 2H)
Reaction SMILES: CN(C)[CH:3]=[O:4].[OH:6][C:7]1[CH:14]=[CH:13][C:12](O)=[CH:11][C:8]=1[CH:9]=[O:10].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([O:6][C:7]1[CH:14]=[CH:13][C:12]([O:4][CH2:3][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:8]=2)=[CH:11][C:8]=1[CH:9]=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cc(O)ccc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=Cc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To an N,N-dimethylformamide (100 mL) solution of 2,5-dihydroxybenzaldehyde (10.0 g, 72.4 mmol) were added sodium hydride (5.79 g, 145 mmol) and benzyl bromide (18.9 mL, 159 mmol) at 0° C., which was stirred at room temperature for 24 hours. Water was added to the reaction solution at 0° C. followed by extraction with ethyl acetate. The organic layer was washed with water and sat. NaCl, followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (17.6 g, 76%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:9][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[O:16][CH2:15][CH2:14][O:10]1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(c2ccc(O)c([N+](=O)[O-])c2)OCCO1

Procedure:
A stirred mixture of 1-(4-hydroxy-3-nitrophenyl)ethanone (3.00 g, 16.56 mmol), ethylene glycol (1.385 mL, 24.84 mmol) and p-toluenesulfonic acid monohydrate (0.158 g, 0.828 mmol) in toluene (60 mL) was heated to reflux for 18 hr in a 250 mL round bottom flask fitted with a Dean-Stark apparatus. The mixture was cooled and diluted with EtOAc (80 mL) and then washed with water (3×30 mL) and brine (20 mL), dried (Na2SO4) and concentrated to dryness in vacuo to afford a thick brown oily residue. This was purified by silica gel chromatography eluting with 5-50% Et2O in isohexane. The title product was isolated as a yellow oil (2.41 g, 64.6%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=2)[CH2:5][C:4](=[O:21])[CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CCN(CC)CC>CN(C1C=CN=CC=1)C>[C:22]([C:3]1[C:2](=[O:1])[CH2:7][CH:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[N:14]=2)[CH2:5][C:4]=1[OH:21])(=[O:24])[CH3:23]
Reactant: COc1cccc(-c2ccsc2C2CC(=O)C=C(O)C2)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2ccsc2C2CC(=O)C(C(C)=O)=C(O)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a 200 mL recovery flask was added 3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone (30F, 4.9 g, 16.3 mmol, 1.0 eq.), CH2CT2 (100 mL), acetic anhydride (2.15 g, 21.1 mmol, 1.3 eq.), Et3N (6.8 mL, 48.8 mmol, 3.0 eq.), and DMAP (catalytic). The reaction mixture was stirred overnight at room temperature whereupon LC/MS showed two signals corresponding to M+H=344. Additional acetic anhydride (0.5 mL, 5.3 mmol, 0.32 eq.) was added and the reaction mixture was heated for 6 h at 40° C. LC/MS analysis showed the reaction to be complete whereupon the mixture was concentrated to a solid and purified via flash chromatography (70% CH2Cl2/Hex to 100% CH2Cl2) to yield a dark orange solid 30G (1.72 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52-2.57 (m, 3H) 2.83 (m, 2H) 3.09 (m, 2H) 3.78 (s, 3H) 4.68 (m, 1H) 6.74 (d, J=8.34 Hz, 1H) 7.32 (d, J=7.33 Hz, 1H) 7.41-7.47 (m, 1H) 7.51 (d, J=5.31 Hz, 1H) 7.76 (t, J=7.96 Hz, 1H). ESI-MS: m/z 344.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C([BH3-])#N.[Na+].[C:49]1(=O)[CH2:52][CH2:51][CH2:50]1.C([O-])(O)=O.[Na+]>CO.CC(O)=O>[CH:49]1([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH:28]2[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31]2)[CH2:52][CH2:51][CH2:50]1
Reactant: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Reactant: O=C1CCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C2CCC2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.84 g, 1.4 mmol) was taken up in methanol (10 ml) and Sodium cyanoborohydride (0.087 g, 1.4 mmol) was added. The pH was adjusted to ca. 6 using a 10% solution of AcOH in MeOH, then Cyclobutanone (0.15 ml, 2.1 mmol) added in one portion. The reaction was stirred at RT for 3 days. NaHCO3 (sat'd) added to the reaction mixture which was then extracted (3×) with DCM. The combined organics were dried with MgSO4, filtered and concentrated. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 4-chlorobenzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (100 mL) was added pyrrolidine (6.55 g, 92 mol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 h. After cooling to 4° C., the resulting precipitate was collected and dried to give 21 g of E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. MS: 291 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>C(O)C>[C:26]1([CH2:25][CH2:24][CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(CCCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4.50 g (22.47 mmol.) of 1-tert-butoxycarbonyl-2,3,5,6-tetrahydro-7H-1,4-diazepine in ethanol (50 ml) were added, at room temperature, 4.7 ml (33.72 mmol.) of triethylamine and 4.47 g (22.45 mmol.) of 1-bromo-3-phenylpropane. The mixture was heated under reflux for 8 hours under nitrogen atmosphere. To the reaction system were further added 4.7 ml (33.72 mmol.) of triethylamine and 4.47 g (22.45 mmol.) of 1-bromo-3-phenylpropane. The mixture was heated for 16 hours under reflux, which was cooled to room temperature. To the reaction system was added ethyl acetate, which was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography. The solvent was distilled off under reduced pressure to give the object compound as a yellow liquid product. The yield was 5.41 g (76%).
Reaction SMILES: [N:1]([CH:4]1[CH2:8][N:7]([C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=2)[C@H:6]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>O1CCCC1>[NH2:1][CH:4]1[CH2:8][N:7]([C:9](=[O:27])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[CH:16][CH:17]=2)[C@H:6]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:5]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)N2CC(N=[N+]=[N-])C[C@H]2C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)N2CC(N)C[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.2 g of benzyl 4-azido-1-[3-(4-tert-butyloxycarbonylaminomethylphenyl)propionyl]prolinate (starting material B3) are dissolved in 50 ml of tetrahydrofuran, and 3.52 g of triphenylphosphine are then added a little at a time, as a result of which a clear evolution of gas can be observed. After 4 h of stirring at RT, 10 ml of water are added, and the mixture is stirred at RT for 6 days. 12.5 ml of 1N hydrochloric acid solution are added, and the mixture is then extracted twice with ethyl acetate. Using 13 ml of 1N sodium hydroxide solution, the aqueous phase is made slightly alkaline, and the phase is then extracted three times with a mixture of ether/methanol (8:2). The extract is dried over magnesium sulfate and then concentrated, and the residue is dried under high vacuum. This gives 2.22 g of the title compound as a viscous oil. The mass spectrum shows the molecular peaks MH+, MNa+ and M2H+ at 482, 504 and 962 Da, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=O)[CH:10](C([O-])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl[C:32](=[CH2:35])[C:33]#[N:34].C(N(CC)CC)C>ClCCl.O>[C:33]([C:32]1[CH:35]=[CH:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)#[N:34]
Reactant: C=C(Cl)C#N
Reactant: CC(C)(C)OC(=O)N1CCN(C=O)C(C(=O)[O-])C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCn2ccc(C#N)c2C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.4 %

Procedure:
To a solution under nitrogen of 28.7 g (102 mmol) of sodium 4-(tert-butyloxycarbonyl)-1-formylpiperazine-2-carboxylate (CAS 1108698-36-7) in 1 l of dichloromethane are added 21.5 g (113 mmol) of p-toluenesulfonyl chloride. After stirring for 40 minutes, 8.2 ml (102 mmol) of 2-chloroacrylonitrile are added. After stirring for 40 minutes, 32.8 ml (235 mmol) of triethylamine are added dropwise and the mixture is stirred overnight at room temperature, and then refluxed for 1 hour. The solution is then cooled to room temperature. 150 ml of water are added. The organic phase is separated out by settling, washed twice with 100 ml of water, dried over sodium sulfate and filtered, and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 0 to 10% ethyl acetate in dichloromethane, to give 17.5 g of tert-butyl 8-cyano-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after dissolving in a mixture of cyclohexane and dichloromethane and then precipitating by slow concentration and drying under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3Cl)[CH:24]=2)=[O:22])[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:24]=2)=[O:22])[CH:13]=1
Reactant: O=C(NCCc1cccnc1)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCc5cccnc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide by a procedure analogous to Example 1C. MS: 428 (MH+); HPLC Rf: 4.34 min.; HPLC purity 99%.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:18](OCC)C>>[CH2:1]([N:5]1[C:9]([CH:10]([OH:11])[CH3:18])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOCC
Reactant: CCCCn1c(C=O)cnc1-c1ccccc1
Product: CCCCn1c(C(C)O)cnc1-c1ccccc1

Procedure:
A solution of aldehyde 102 (230 mg) in diethyl ether (30 mL) is placed in a separatory funnel and treated with a solution of Preparation of 1-(1-Butyl)-2-phenyl-5-(1-[N-[{3,4-methylenedioxyphenylmethyl]}-N-[phenylmethyl]aminoethylimidazole) methyl lithium (1.4 M in THF, 1.5 ml). After 10 min. the solution is washed with ammonium chloride solution (1 M, 20 ml), dried (Na2SO4) and concentrated. The resulting dark oil is purified by preparative TLC (10% MeOH/CHCl3) to provide compound 107 as a colorless oil (180 mg). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=2 Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86 (q, J=7 Hz, 1H), 4.18 (m, 1H), 4.0 (m, 1H), 1.63 (d, J=6.6 Hz, 3H), 1.63 (m, 2H), 1.23 (m, 2H), 0.81 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:34](=[O:36])[CH3:35])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1.02 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 10 ml of acetic anhydride and one ml of pyridine is stirred at 100° C. for 3 hours. Then, the mixture is evaporated under reduced pressure. Benzene is added to the mixture, and the mixture is evaporated to remove solvent. 0.65 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:15]O>>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: CO
Agent: Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1Br

Procedure:
100 g (406 mmol) of 2-bromo-3-nitrobenzoic acid, 22 g (609 mmol) of conc. HCl and 1 l of methanol are heated under reflux for 24 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is recrystallised from ethanol. Yield: 94.6 g (363 mmol), 89.5% of theory.
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](F)(F)[CH:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].[Si](=O)=[O:17].S(=O)(=O)(O)O>>[F:7][C:6]([F:9])([F:8])[CH:5]([C:10]([F:13])([F:12])[F:11])[C:4]([O:3][CH2:2][Cl:1])=[O:17]
Reactant: O=[Si]=O
Reactant: FC(F)(F)C(C(F)(F)F)C(F)(F)OCCl
Agent: O=S(=O)(O)O
Product: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Reaction time: 21 h
Yield: 92.8 %

Procedure:
In a four necked 1 liter flask equipped with a thermometer, a condenser and a stirrer, 1-chloromethoxy-1,1-difluoro-2-trifluoromethyl-3,3,3-trifluoropropane (276.6 g, 1.04 mol) and silicon dioxide (50.8 g, 0.85 mol) were charged, and concentrated sulfuric acid (60 g, 0.61 mol) was dropwise added thereto while stirring. The reaction was continued at 110° C. for 21 hours. Then, the reaction mixture was distilled to give monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (192.9 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[N:9]1([CH2:15][CH2:16][CH2:17][C:18]#N)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)(C(F)(F)F)=[O:21].CC#N>CCOCC.C(Cl)Cl>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18](=[O:21])[CH2:17][CH2:16][CH2:15][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccccc1I
Reactant: N#CCCCN1CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccccc1C(=O)CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10 mL oven-dried flask was added Mg turnings (97 mg, 4.1 mmol) which was activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a suspension of 2-iodo-toluene (380 mL, 3.0 mmol) in Et2O (3 mL) and the reaction mixture was allowed to reflux for 1 hours. A suspension of 4-piperidin-1-yl-butanenitrile 10 (Dahlbom et. al. Acta. Chem. Scand. 1951, 5, 690-697) (0.305 mg, 2.0 mmol) in CH2Cl2 (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and stirred at rt for 12 hours followed by addition of NaOH (12 mL, 2 M). Addition of THF (15 mL) was followed by extraction with ethyl acetate (3×50 mL), and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and dried (MgSO4) and evaporated to dryness to produce 0.21 g of crude 11. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN+0.1%TFA] to produce an analytically pure sample of compound 11; LC-MS [M+H]+ 245 (cald. 245.2).
Reaction SMILES: [CH3:1][C:2]1([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:7][CH2:6][N:5]([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:5]5[CH2:6][CH2:7][C:2]([CH3:1])([O:29][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:37]([CH3:39])[CH3:38])[CH2:3][CH2:4]5)=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(C)(O[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Yield: 93 %

Procedure:
A solution of Intermediate 79e (160 mg, 0.291 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 176 mg, 0.437 mmol) and DIPEA (150 mg, 1.16 mmol) in DMF (4 mL) was stirred at 50° C. for 1 h. The reaction mixture was diluted with EtOAc and washed with water (2×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound (210 mg, 93%). LCMS (Method 4): Rt 5.32 min, m/z 805 [MH+].