Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:38][OH:39].C[O-].[K+].Cl>CO>[OH:39][NH:38][C:17](=[O:19])/[CH:16]=[CH:15]/[C:12]1[CH:11]=[CH:10][C:9]([N:8]([C@@H:22]2[CH2:26][CH2:25][N:24]([CH:27]3[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH2:32]3)[CH2:23]2)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[N:14][CH:13]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(C3CC(C)(C)NC(C)(C)C3)C2)nc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CC1(C)CC(N2CC[C@@H](N(C(=O)OC(C)(C)C)c3ccc(/C=C/C(=O)NO)cn3)C2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (265 mg, 0.529 mmol) in methanol (5 mL) was added hydroxylamine hydrochloride (184 mg, 2.65 mmol) at ambient temperature. To this mixture was added 1N potassium methoxide in methanol (5.29 mL, 5.29 mmol) dropwise in an ice bath and the resulting mixture was stirred at ambient temperature for three hours. To the mixture was added 1N hydrogen chloride to neutralize the solution. The solvent was removed in vacuo and the residue was desalted using ion-exchange resin. The crude product was purified by preparative high-pressure liquid chromatography to afford tert-butyl {5-[(1E)-3-(hydroxyamino)-3-oxo-1-propen-1-yl]-2-pyridinyl}[(3R)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-3-pyrrolidinyl]carbamate (103 mg) as a colorless wax.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:17][CH3:18])[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:3].[CH3:19][S:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=3)[S:29][C:28]=2[CH:43]=1)(=[O:22])=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>>[ClH:1].[CH2:17]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:31]2[C:27]3[CH:26]=[CH:25][C:24]([O:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:43][C:28]=3[S:29][C:30]=2[C:32]2[CH:33]=[CH:34][C:35]([O:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:36][CH:37]=2)=[O:14])=[CH:15][CH:16]=1)[CH3:18]
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Reactant: CCN(CC)CCOc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OS(C)(=O)=O)cc3)sc3cc(OS(C)(=O)=O)ccc23)cc1
Reaction time: 1.5 h

Procedure:
A 5.2 g. portion of 4-(2-diethylaminoethoxy)benzoic acid, hydrochloride, was converted to the acid chloride, and used to acylate 5 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene according to the process of Example 5. The amount of aluminum chloride was 15.1 g., and the reaction mixture was stirred for 1.5 hours after its addition. The mixture was worked up as described in Example 5 to obtain a yellow foam, which began to crystallize after standing for several days. It was triturated with denatured ethanol and recrystallized from denatured ethanol to obtain 6.5 g. of purified crystalline product, m.p. 172°-174°.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(S)o1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cc1nnc(SCCCC(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)o1
Yield: 79 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-5-methyl -1,3,4-oxadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 79% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[N:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[C:5]=1O)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[S:10][CH:11]=[CH:12][C:6]=12
Reactant: O=[N+]([O-])c1cnc2sccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2sccc2c1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To 5-nitrothieno[2,3-b]pyridin-4-ol (607.9 mg, 3.099 mmol), POCl3 (6.00 mL) was added, then the mixture was stirred at 110° C. for 1 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in DCM (50 mL), and a saturated aq. NaHCO3 (50 mL) was added slowly. The organic layer was washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 50% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (605.3 mg, 91%). LCMS calc. for C7H4ClN2O2S (M+H)+: m/z=215.0. found 215.0.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]=O)(=[O:3])[CH3:2].CC([O-])=O.[Na+].Cl.[NH2:24][OH:25]>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]=[N:24][OH:25])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A soln. of 2-(3,5-dichloro-2-formylphenoxy)ethyl acetate (1.48 mmol) in 2.5 mL DMF was cooled to 0° C. and NaOAc (1.62 mmol) followed by hydroxylamine HCl (1.62 mmol) were added. The ice bath was removed and the reaction mixture was stirred at RT for 1.5 h. The mixture was diluted with EtOAc and washed once with water and brine. The comb. org. layers were dried over MgSO4 and conc. in vacuo. Purification with CC using Hept and EtOAc gives the desired compound as white solid.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:20](=[O:21])[CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Thioanisole (6.22 g, 50 mmol) I) diliuted with CH2Cl2 (5 ml) is added to a suspension of AlCl3. (6.8 g, 51 mmol) in 45 ml of CH2Cl2. Phenylacetyl chloride (7.73 g, 50.0 mmol) in CH2Cl2 (15 ml) is added dropwise at 0° C. over 5 min. Then, the reaction solution is gradually warmed up to room temperature and stirred overnight. The reaction solution is poured onto ice. The resulting white precipitate is extracted with CH2Cl2, and the organic layer is washed with water and NaHCO3 aq. solution, followed by drying over anhydrous MgSO4. After evaporating the solvent, the residue is purified by recrystallization from hexane-CH2Cl2. 10.4 g of a white solid are obtained (86%). 1H NMR (CDCl3), δ[ppm]: d 2.50 (s, 3H), 4.23 (s, 2H), 7.22-7.27 (m, 5H), 7.32 (t, 2H), 7.91 (d, 2H)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15](O)=[O:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of azetidine-1,3-dicarboxylic acid monobenzyl ester (6.4 g) in THF (200 mL) was added BH3.THF (6 eq, 163 mL, 1M solution) dropwise via an addition funnel at −40 C under an N2 atmosphere. The solution was warmed to RT and stirred overnight. To the reaction, 5N NaOH (50 mL) was added and then concentrated under vacuum. The resulting aqueous solution was extracted with Et2O (3×100 mL). The organic layer was dried over Na2SO4 and evaporated to give the title compound which was used without further purification.
Reaction SMILES: [O:1]=[C:2]([CH3:11])[C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO.S(OC)(O[CH3:18])(=O)=O>C(=O)([O-])[O-].[Na+].[Na+].O>[O:1]=[C:2]([CH3:11])[C:3](=[N:9][O:10][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(=NOC)C(C)=O
Yield: 82.7 %

Procedure:
In a solution of 13.3 g of sodium carbonate in 120 ml of water is dissolved 10 g of ethyl 3-oxo-2-hydroxyiminobutyrate, followed by addition of 30 ml of methanol. The mixture is cooled with ice and, under stirring, 15.8 g of dimethyl sulfate is added dropwise over a period of 3 minutes. After the dropwise addition has been completed, the ice-bath is removed and the mixture is stirred at room temperature for 40 minutes. The reaction mixture (pH 8 or higher) is extracted twice with ethyl acetate and the extracts are pooled, washed with water and dried. The solvent is then evaporated off under reduced pressure and the residue is subjected to distillation under reduced pressure. By the above procedure is obtained 9 g of ethyl 3-oxo-2-methoxyiminobutyrate as a pale-yellow oil boiling at 56°-61° C./0.3-0.4 mmHg.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.C[O:34][B:35](OC)[O:36]C>C1COCC1>[C:27]1([C:13]([C:10]2[CH:11]=[CH:12][C:7]([B:35]([OH:36])[OH:34])=[CH:8][CH:9]=2)=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
Into a 250 mL two-necked round-bottom flask under nitrogen was slowly added n-butyllithium (1.6 M in hexane, 7.5 mL, 12 mmol) and a THF solution (80 mL) of 1-(4-bromophenyl)-1,2,2-triphenylethene (3) (4.11 g, 10 mmol) at −78° C. After stirring for 3 h, 2.4 mL of trimethylborate (20 mmol) was added into the reaction mixture. The mixture was warmed to room temperature and the reaction was terminated by adding hydrochloric acid (2 M, 10 mL) after 12 h. The mixture was then poured into water and extracted with dichloromethane. The organic layer was washed with water and dried over magnesium sulfate. After filtration and solvent evaporation, the residue was purified by silica-gel column chromatography using n-hexane/ethyl acetate as eluent. White solid of 4-(1,2,2-Triphenylvinyl)phenylboronic acid (4) was obtained in 70% yield (2.6 g). 1H NMR (300 MHz, CDCl3), δ (TMS, ppm): 7.88 (d, 2H, J=8.1 Hz), 7.13-7.00 (m, 17H), 4.49 (s, 1H). 13C NMR (75 MHz, CDCl3), δ (TMS, ppm): 148.9, 144.2, 144.1, 144.09, 142.4, 141.4, 135.6, 133.5, 132.0, 131.6, 128.4, 128.3, 127.4, 127.2. HRMS (TOF): m/e 376.2030 (M+, calcd 376.1635).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[N:3]=1.Cl[CH2:13][CH:14]=O>C(O)C.O>[Br:1][C:2]1[N:3]=[C:4]([NH:8][C:9]2[S:10][CH:13]=[CH:14][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCl
Reactant: NC(=S)Nc1cccc(Br)n1
Solvent: O
Solvent: CCO
Product: Brc1cccc(Nc2nccs2)n1
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
A suspension of 2-bromo-6-thioureidopyridine (3 g, 12.92 mmol) and chloroacetaldehyde (3.28 mL, 25.85 mmol) in ethanol (27 mL) and water (7 mL) was heated at reflux for 4.75 h. The solution was concentrated in vacuo and the residue was diluted with 1 N aqueous NaOH solution at 0° C., stirred for 10 min, and the pH was then adjusted to 8.5 by addition of 6 N aqueous HCl solution. The precipitate was collected by filtration, washed several times with water and dried in vacuo over P2O5 to obtain the titled compound (3.17 g, 96%) as a light yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13](Br)=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][NH:29][C:28](=[O:32])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([N:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:27][C:28]2=[O:32])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 49 %

Procedure:
Following the procedure as described in Example 8, making variations only as required to use N-benzyl-5-bromo-3-methylthiophene-2-carboxamide in place of N-benzyl-5-bromothiophene-3-carboxamide to react with 4-(benzyloxy)pyridin-2(1H)-one, the title compound was obtained as colorless solid in 49% yield: mp 153-154° C.; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=7.9 Hz, 1H), 7.43-7.27 (m, 10H), 6.84 (s, 1H), 6.20-6.11 (m, 2H), 6.05 (d, J=2.7 Hz, 1H), 5.03 (s, 2H), 4.59 (d, J=5.7 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 162.5, 161.9, 139.2, 137.6, 134.2, 128.43, 128.40, 128.3, 127.5, 127.4, 127.2, 126.7, 121.8, 102.9, 97.8, 70.3, 43.6, 15.6; MS (ES+) m/z 431.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[CH:33][N:32]=1>CS(C)=O>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[O:19][C:31]3[N:32]=[CH:33][CH:34]=[CH:35][C:36]=3[C:37]#[N:38])=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)cc21
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(Oc4ncccc4C#N)c3)cc21
Reaction time: 0.33 h

Procedure:
A solution of 1-(2,2-dimethylpropyl)-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-179, 23 mg, 0.07 mmol) in DMSO (2 ml) was charged with Potassium carbonate (20.5 mg, 0.15 mmol, 2.0 eq) and 2-Chloro-3-cyanopyridine (15.4 mg, 0.11 mmol, 1.5 eq). The mixture was irradiated in a microwave at 160 deg C. for 20 min. The resulting dark mixture was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present), providing the title compound, 2-{3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]phenoxy} nicotinonitrile (2-1), as a tan solid-oil. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, 1H, J=3.3 Hz), 8.03 (d, 1H, J=5.9 Hz), 7.51-7.50 (m, 2H), 7.42 (s, 1H), 7.32 (d, 1H, J=8.2 Hz), 7.20-7.17 (m, 2H), 7.13-7.09 (m, 2H), 3.70 (s, 2H), 3.49 (s, 3H), 1.06 (s, 9H). LRMS m/z: Calc'd for C25H24N4O2(M+H) 413.4, found 413.2.
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[CH:15][S:16][CH:17]=2)[C:5](=[CH:12][C:13]#[N:14])[C:6]2[C:7](=[CH:9][S:10][CH:11]=2)[N:8]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:13]([CH:12]=[C:5]1[C:4]2=[CH:15][S:16][CH:17]=[C:3]2[C:2]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[N:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]12)#[N:14]
Reactant: N#CC=C1c2cscc2N=C(Cl)c2cscc21
Reactant: CN1CCNCC1
Product: CN1CCN(C2=Nc3cscc3C(=CC#N)c3cscc32)CC1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
50 ml of N-methyl-piperazine are added to 14.4 g (52 mmoles) of 5-chloro-9-cyanomethylene-dithieno[3,4-b:4',3'-e]azepine and the mixture is stirred under nitrogen at 110° C. for 2 to 3 hours. After having been cooled, the dark homogeneous reaction mixture is poured onto ice-water and the yellowish crude 9-cyanomethylene-5-(4-methyl-piperazin-1-yl)-dithieno[3,4-b:4',3'-e]azepine is filtered off with suction. After the crude product has been dried in an oven under reduced pressure, it is recrystallized from ethanol, with the addition of active charcoal, or purified by column chromatography (silica gel, mobile phase: a 95/5 mixture of methylene chloride and methanol). 13.6 g (85%) of yellowish 9-cyanomethylene-5-(4-methyl-piperazin-1-yl)-dithieno[3,4-b:4',3'-e]azepine are obtained in the form of a cis/trans-isomer mixture of melting point 148°-151° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Br-:24].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:24][CH2:20][C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=1)=[O:21]
Reactant: [Br-]
Reactant: CC(=O)c1cccc(OCCCOCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc(OCCCOCc2ccccc2)c1

Procedure:
To a solution of 1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone (10.59 g) in tetrahydrofuran (50 mL) was added methanol (50 mL) and a solution of tetrabutylammonium tribromide (16 g) in tetrahydrofuran (50 mL). The reaction was stirred at ambient temperature for 45 min at which time tetrabutylammonium tribromide (0.89 g) was added, followed by further addition of 0.6 g. 10% aqueous sodium thiosulfate was added to the reaction and the mixture was concentrated in vacuo to a minimum volume. Ethyl acetate was added and the resultant organic solution was washed with aqueous sodium thiosulfate, saturated sodium bicarbonate and brine and concentrated to an oil to afford the title compound.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10](Br)=[CH:9][N:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Br:6][C:7]1[N:8]=[CH:9][C:10]([CH:18]([C:17]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:16]=2[F:15])[OH:19])=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: O=Cc1cc(F)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(Br)ncc1C(O)c1cc(F)ccc1F
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
In an argon atmosphere, a hexane solution of n-butyllithium M, 8.22 ml, 13.2 mmol) was added to a solution of 2,5-dibromo-4-methylpyridine (3.00 g, 12.0 mmol) in diethyl ether (120 ml) at −78° C. After stirring the reaction mixture for 30 minutes, 2,5-difluorobenzaldehyde (1.34 ml, 12.0 mmol) was added. After stirring for 1 hour at the same temperature, saturated aqueous ammonium chloride was added at room temperature. After the organic layer was separated, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=4:1 was concentrated under reduced pressure, to obtain the title compound (1.26 g, 4.01 mmol, 34%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)C2CCOCC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=360.1, tR (minutes, Method F)=1.97
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]([OH:17])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>C(Cl)Cl>[CH3:18][NH:19][C:15]([C@H:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:17]
Reactant: O=C(O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To (R)-1-(4-Nitro-phenyl)-pyrrolidine-2-carboxylic acid (Method 55; 1.8 g, 7.6 mmol) in DCM (50 ml) was added HATU (3.2 g, 8.4 mmol) and DIPEA (2.0 ml, 11.4 mmol). The reaction was stirred for 10 minutes before the addition of methylamine (2.0 N in THF, 5.0 ml, 15 mmol); the reaction was stirred for 1 hour before being quenched with water (50 ml). The reaction was extracted with DCM (3×100 ml), dried and solvent removed in vacuo to yield a yellow gum. Purification was achieved via column chromatography eluting with 20% EtOAc/isohexane, 60% EtOAc/isohexane and finally 100% EtOAc. The title compound was obtained as an orange gum; (1.4 g, 74%). NMR (299.954 MHz, CDCl3) 8.10 (d, 2H), 6.56 (d, 2H), 6.24 (s, 1H), 4.20 (t, 1H), 3.75 (t, 1H), 3.40 (q, 1H), 2.80 (d, 3H), 2.36-2.29 (m, 2H), 2.13-2.05 (m, 2H); m/z 250.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13].[NH2:33][OH:34].[NH4+].[Cl-]>C1COCC1>[OH:34][NH:33][CH:10]([CH2:9][CH2:8][CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:25][N:26]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: NO
Reactant: O=S(=O)(/C=C/CCCc1ncccn1)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred solution of 2-(4-{[(1E)-5-pyrimidin-2-ylpent-1-en-1-yl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine (8.79 g, 18.6 mmol) in THF (90 mL) was added 50% aqueous solution of hydroxylamine (18 mL) and the reaction stirred at room temperature for 2 hours. A saturated solution of NH4Cl (200 mL) was then added and then this was extracted twice with extracted with EtOAc (2×250 mL), combined organics washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-{[2-(hydroxyamino)-5-pyrimidin-2-ylpentyl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine as a pale yellow solid (8.96 g, 17.7 mmol, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N+:6]([O-:8])[CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:16])=[O:10])=[N+:6]([O-:8])[CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c[n+]1[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c[n+]1[O-]

Procedure:
To a solution of 5-bromo-2-carboxypyridine 1-oxide (19.6 g) in methanol (300 mL) was added dropwise thionyl chloride (37.1 g) at 0° C., and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (22.0 g) as a crude amorphous solid. This compound was used for the next step without further purification.