Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:20][CH3:21])[C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH:10]([CH3:12])[CH3:11]
Reactant: CCI
Reactant: CC(C)c1c(Cl)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Cl)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 0.67 h

Procedure:
6-Chloro-5-isopropyl-1H-pyrimidine-2,4-dione (18.8 g, 100 mmol) was stirred with anhydrous powdered potassium carbonate (16.56 g, 120 mmol) in DMF (200 mL) at room temperature. After 40 min., iodoethane (8 mL, 100 mmol) was added and the mixture was stirred overnight. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (from 1:4 to 1:2)) to give 13.8 (63%) of 6-chloro-1-ethyl-5-isopropyl-1H-pyrimidine-2,4-dione as a white solid. m.p. 160-161° C.; 1H-NMR (200 MHz, CDCl3) δ 1.28-1.35 (9H, m), 3.22 (1H, m), 4.15 (2H, q, J=7.2 Hz); m/z (EI) 216 (M+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[CH2:32][C:16]4([CH2:31][C:18]5([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]5)[CH2:17]4)[O:15][C:12]3=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[C-]#N.[K+].C([O-])(=O)C.[CH3:40][N:41](C)C=O>[Cu](Br)Br.O>[C:40]([C:7]1[CH:8]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:9]1[CH:10]=[C:11]2[CH2:32][C:16]3([CH2:17][C:18]4([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]4)[CH2:31]3)[O:15][C:12]2=[CH:13][N:14]=1)#[N:41]
Reactant: CN(C)C=O
Reactant: CSc1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cc1
Agent: Br[Cu]Br
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: O
Product: CSc1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)c(C#N)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(4-methylsulfanyl-phenyl)-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (100 mg), potassium cyanide (22 mg), copper(II) bromide (20 mg), palldium(II) acetate (5 mg), and N,N-dimethylformamide (5 mL) is stirred in air at 130° C. overnight. After cooling to room temperature, water is added and the mixture is extracted with ethyl acetate. The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 3): tR=1.17 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: Cl.N[C@H](C)CSC1SC=CC=1.SC1SC=CC=1.C([O:21][C@@H:22]1[C@H:26]([O:27]C(=O)C)[C@@H:25]([CH2:31][O:32]C(=O)C)[O:24][C@H:23]1[N:36]1[C:54]2[N:53]=[C:52]([Cl:55])[N:51]=[C:40]([NH:41][C@H:42]([CH3:50])[CH2:43][S:44][C:45]3[S:46][CH:47]=[CH:48][CH:49]=3)[C:39]=2[N:38]=[CH:37]1)(=O)C.C[O-].[Na+]>CO>[Cl:55][C:52]1[N:51]=[C:40]([NH:41][C@H:42]([CH3:50])[CH2:43][S:44][C:45]2[S:46][CH:47]=[CH:48][CH:49]=2)[C:39]2[N:38]=[CH:37][N:36]([C:54]=2[N:53]=1)[C@@H:23]1[O:24][C@H:25]([CH2:31][OH:32])[C@@H:26]([OH:27])[C@H:22]1[OH:21]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4cccs4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@@H](N)CSc1cccs1
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: C[C@H](CSc1cccs1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 82 %

Procedure:
The title compound was prepared according to method A as described in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]thiophene hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (7.53 g, 43 mmol) and 2-mercaptothiophene (5.00 g, 43 mmol) followed by acidic hydrolysis] (0.63 g, 3.0 mmol) with 9-(2,3,5-tri-O-acetyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.12 g, 2.5 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(2-thienyl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title 2-chloro-N-[(R)-1-(2-thienyl)thio-2-propyl]adenosine (0.95 g, 82%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ 1.26 (3H, d, --CHCH3), 2.95-3.18 (2H, ABX, --CH2 --S--), 3.55 and 3.61 (2H, ABX, H-5'a and H-5'b), 3.95 (1H, q, H-4), 4.14 (1H, t, H-3'), 4.44 (1H, m, --CHCH3), 4.54 (1H, t, H-2'), 5.84 (1H, d, H-1'), 7.03 (1H, t, Ar-H), 7.23, 7.61 (2H, 2d, Ar-H), 8.38 (1H, d,-NH), 8.42 (1H, s, H-2). HPLC retention time 19.5 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][C:11]=1[CH3:12].[OH-].[Na+].CN([CH:18]=[O:19])C>O>[CH3:12][C:11]1[CH:10]=[C:9]([CH:18]=[O:19])[O:8][C:7]=1[CH3:6]
Reactant: Cc1ccoc1C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)oc1C
Reaction time: 3 h
Yield: 76 %

Procedure:
According to the procedure of S. F. Martin, et al. J. Org. Chem. 1984, 49, 2512-2516, phosphorus oxychloride (10.7 mL, 114.4 mmol) was added dropwise to a stirred, ambient temperature solution of 2,3-dimethylfuran (10 g, 104 mmol) in DMF (150 mL) under a dry nitrogen atmosphere over a period of 30 min. After 3 h., the reaction mixture was hydrolized with 2.5 N aq. sodium hydroxide and further diluted with water (50 mL). Aqueous mixture was extracted with dichloromethane (2×300 mL). The combined dichloromethane extracts were washed with water, dried with brine and purified by silica gel flash chromatography (eluent: ethyl acetate) to provide a yellow oil (9.8 g, 76%); MS (ESI): [M+H]+, 125.1.
Reaction SMILES: [H-].[Na+].P([CH2:11][C:12]#[N:13])(OCC)(OCC)=O.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH2:21][C:22](=O)[C:18]=2[CH:17]=1>C1COCC1>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH:21]=[C:22]([CH2:11][C:12]#[N:13])[C:18]=2[CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc2c(c1)C(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2occ(CC#N)c2c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Under inert atmosphere, 83 mmol of sodium hydride are suspended in 100 ml of anhydrous THF. The temperature is cooled at -15° C. and 83 mmol (14.7 g) of (EtO)2POCH2CN in 50 ml of 1BF are dropply added. Then 55 mmol (9 g) of compound obtained in stage A in 100 ml of THF are dropwised at -15° C. The solution is stirred during 2 hours at that temperature before being hydrolysed. The mixture is extracted with ethyl acetate and the organic layers are washed with brine, dried over magnesium sulfate and concentrated. The title product is obtained after purification by chromatography on silica gel.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)[OH:16].O.C(Cl)Cl>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[C:12]([OH:16])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
190 mg of α-(p-isobutylphenyl)-propionaldehyd are dissolved in 15 ml of acetone, and the solution cooled to -25° C is added to 220 ml of a solution containing 30 g chromiumtrioxide, 25 ml of concentrated sulfuric acid and water per 100 ml. The whole stirred for one hour at -25° C, the temperature was allowed to rise to about 0° C while stirring and then the reaction mixture was poured into a mixture of 20 ml water and 60 ml of methylene chloride. The two phases are separated and the watery phase washed two times with 30 ml of methylene chloride each time. The organic layers are dryed over magnesiumsulfat and evaporated. These were obtained 157 mg of α-(p-isobutylphenyl)-propionic acid, which melted after recrystallisation from few hexane at 74°-75.5°. This compound is known as "IBUPROFEN" and is used as antiinflammatory agent (cf. Brit. Pat. No. 971,700 and French Pat. No. 1,545,270).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[C:26]([CH3:34])=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=3)[C:30]#[N:31])[C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[C:36]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[C:29]([C:30]#[N:31])[C:28]([Cl:33])=[CH:27][C:26]=1[CH3:34])([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1cc(Cl)c(C#N)cc1N[C@@H](c1nnc(-c2ccc(N)cc2)o1)[C@H](C)O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Cl)c(C#N)cc1N[C@@H](c1nnc(-c2ccc(NC(=O)c3ccccc3)cc2)o1)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a pre-cooled (0° C.) solution of 5-((1R,2S)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-4-methylbenzonitrile (290 mg, 0.58 mmol) in CH2Cl2 (10.0 mL) and pyridine (1.2 mL) was added, portion wise, acetyl chloride (0.34 mL, 2.9 mmol). Upon complete addition the reaction mixture was warmed slowly to room temperature and stirred for 23 h. The reaction mixture was then cooled to 0° C. and quenched with 10% aq HCl (5 mL) then H2O (15 mL) was added. The solution was extracted with CH2Cl2 (2×40 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange oil, which was used without further purification (400 mg). 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.36 (d, J=8.4 Hz, 2H), 8.27 (br s, 1H), 8.16 (d, J=8.6 Hz, 2H), 8.08 (d, J=8.2 Hz, 1H), 8.02 (d, J=8.6 Hz, 2H), 7.94-7.83 (m, 3H), 7.53 (d, J=8.2 Hz, 1H), 5.57 (d, J=8.9 Hz, 1H), 4.99 (dd, J=1.8, 8.9 Hz, 1H), 4.76-4.68 (m, 1H), 2.58 (s, 3H), 1.61 (d, J=6.3 Hz, 3H), 1.09 (s, 9H), 0.26 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: C(C(N1CCNCC1)C1C=CC(OC)=CC=1)#N.CO.[Cl:20]C(OCC)=O.[C:26]([CH:28]([N:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)#[N:27]>C1C=CC=CC=1>[ClH:20].[C:26]([CH:28]([N:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1)[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)#[N:27]
Reactant: CCOC(=O)Cl
Agent: CCOC(=O)N1CCN(C(C#N)c2ccc(OC)cc2)CC1
Agent: COc1ccc(C(C#N)N2CCNCC2)cc1
Solvent: CO
Solvent: c1ccccc1
Product: Cl
Reaction time: 2 h

Procedure:
In a 100-ml. three necked flask was placed 11.5 g. of N-(α-cyano-4-methoxybenzyl)piperazine and 40 ml. of methanol to obtain a homogenous solution. To the resulting solution was added dropwise 5.96 g. of ethyl chloroformate over a period of about 70 minutes with stirring while the temperature was kept at about 20°C. After dropping, the internal temperature was raised to 40° to 45°C., and then the mixture was further stirred for 2 hours. The solution was concentrated under reduced pressure and 500 ml. of water was added thereto. This solution was made alkaline with the aid of sodium carbonate with cooling and extracted with benzene. The benzene layer was washed with dilute hydrochloric acid and water, and dried over sodium sulfate. The solvent was distilled off to afford 9.7 g. of N-(α-cyano-4-methoxybenzyl)-N'-ethoxycarbonylpiperazine as an oily substance. This product was dissolved in benzene and the resultant solution was saturated with dry hydrochloric gas to separate crystal which was collected by filtration. Recrystallization from acetone afforded N-(α-cyano-4-methoxybenzyl)-N' -ethoxycarbonylpiperazine hydrochloride having a melting point of 170°C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:10]=[CH:11][C:12]=2[N+:13]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH4+].[Cl-].[C:25]([C:27]1[O:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1)#[N:26].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CCO.O.ClCCl.[Fe].CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[C:9]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:10]=[CH:11][C:12]=2[NH:13][C:32]([C:30]2[O:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(C3=CCCCC3)c2)CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Fe]
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(NC(=O)c3ccc(C#N)o3)c(C3=CCCCC3)c2)CC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 72.5 %

Procedure:
To 122 mg (0.299 mmol based on 74% purity) of 1-(3-cyclohex-1-enyl-4-nitro-phenyl)-4-methyl-piperazine (as prepared in the previous step) in 5.0 mL of EtOH-water (2:1) was added 83.8 mg (1.50 mmol) of iron powder and 160 mg (2.99 mmol) of NH4Cl and the mixture refluxed under Ar for 12 h. An additional 83.8 mg (1.50 mmol) of iron powder was added, and the mixture was refluxed for 1 h. The mixture was poured into EtOAc (12 mL), filtered (Celite), washed with EtOAc (2×4 mL), concentrated in vacuo and dissolved in anh THF (4.0 mL). The resulting aniline solution was placed under Ar and used immediately in the following reaction. 61.6 mg (0.449 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1) in 2.5 mL of anh dichloromethane under a CaSO4 drying tube was treated with 60.0 μL (0.688 mmol) of oxalyl chloride followed by 10 μL of anh DMF. The solution was stirred for 25 min and quickly concentrated in vacuo at 20-25° C. The residue was placed under high vacuum for 2-3 min and then immediately placed under Ar, cooled to 0° C. in an ice bath and treated with the aniline solution produced above followed by 104 μL (0.598 mmol) of DIEA. After stirring 30 min at RT, the mixture was concentrated in vacuo, dissolved in EtOAc (20 mL), washed with 1M K2CO3 (2×10 mL) and brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was chromatographed on a 10-g silica SPE column with 1-4% MeOH-dichloromethane to give a yellow resin which was then crystallized from Et2O-hexane to afford 84.7 mg (72%) of the title compound as a crystalline yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.57 (br s, 1H), 8.26 (d, 1H, J=9.0 Hz), 7.20, 7.23 (AB q, 2H, J=3.7 Hz), 6.86 (dd, 1H, J=9.0, 2.9 Hz), 6.74 (d, 1H, J=2.9 Hz), 5.84-5.85 (m, 1H), 3.20-3.22 (m, 4H), 2.57-2.59 (m, 4H), 2.36 (s, 3H), 2.23-2.30 (m, 4H) and 1.79-1.84 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H26N4O2, 391.2 (M+H). found 391.2.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:25][NH2:26].C(O)(=O)C>C(O)C>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)=[N:26][NH:25][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(C)cc1)OCO2
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(4-methylbenzoyl)phenylacetate (90 mg, 0.29 mmol), hydrazine hydrate (50 μL, 0.88 mmol) and acetic acid (40 μL) in ethanol (10 mL), mp: 222°-224° C. 1H NMR (CDCl3) 8.36 (s, 1H), 7.48 (d, 2H, J=8.0), 7.23 (d, 2H, J=8.0), 6.82 (s, 1H), 6.64 (s, 1H), 6.02 (s, 2H), 3.45 (s, 2H), 2.41 (s, 3H). Anal. Calcd. for C17H14N2O3 : C, 69.38; H, 4.79; N, 9.52. Found: C, 69.14; H, 4.80; N, 9.30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI.O>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: O
Product: COc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 157.5 %

Procedure:
2-Chloro-4-fluoro-5-nitrophenol (9.6 g) and potassium carbonate (3.8 g) were stirred in acetonitrile (50 ml). Methyl iodide (14 g) was added thereto and refluxed for 3 hours. Water was added to the reaction mixture, followed by extraction with ether. The ether extract was washed with water, dried and concentrated. The residue was recrystallized from ethanol to obtain 8.9 g of 4-chloro-2-fluoro-5-methoxynitrobenzene. M.P., 67.5°-69.8° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14]1.C(O)(=O)C>C(Cl)Cl.CO.CC(N(C)C)=O>[S:13]1[CH:17]=[CH:16][C:15]([CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=2)=[CH:14]1
Reactant: CCCC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccsc1
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: ClCCl
Product: CCCC(=O)c1ccc(NCc2ccsc2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, to a solution of 1-(4-aminophenyl)-butan-1-one (19.64 mg, 0.1 mmol) in DCM/MeOH (0.7 mL) was added a solution of thiophene-3-carbaldehyde (22.4 mg, 0.2 mmol) in DMA (0.8 mL). A solution of acetic acid (18 mg, 0.3 mmol) in DCM/MeOH (0.7 mL) was added, followed by the addition of 160 mg of MP-CNBH3 resin (3 eq.; subst. 2.25 mmoles/g). The vial was capped and was then heated with shaking overnight at 55° C. The progress of the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH. Purification by reverse phase HPLC (TFA method) gave the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH3:54])=[C:48]([C:55]#[N:56])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[C:55]([C:48]1[CH:47]=[CH:46][C:51]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:50][C:49]=1[O:52][CH2:53][CH3:54])#[N:56]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOc1ccc(OB([O-])[O-])cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOc1cc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (10/1/1, 19.2 ml) and then were added 3-cyano-4-ethoxyphenyl borate (205 mg) and potassium carbonate (251 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (48 mg), and the mixture was refluxed for 18 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-cyano-3-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 93) (209 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[CH:10]=[C:11]2[N:15]([N:16]=1)[C:14]([C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([N+:25]([O-:27])=[O:26])[C:18]=1[CH3:28])=[N:13][NH:12]2)([CH3:8])([CH3:7])[CH3:6].CO>C1COCC1.N1C=CC=CC=1>[C:1]([N:12]1[C:11]2=[CH:10][C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])=[N:16][N:15]2[C:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([N+:25]([O-:27])=[O:26])[C:18]=2[CH3:28])=[N:13]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1-c1n[nH]c2cc(C(C)(C)C)nn12
Reactant: CC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)n1nc(-c2c(C)cc(C)c([N+](=O)[O-])c2C)n2nc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Acetyl chloride (12 g, 154 mmole) in THF (80 ml) was added dropwise to a stirred solution of Coupler 1 (22.5 g, 65.2 mmole) in pyridine (110 ml) keeping the temperature below 15° C. The reaction mixture was stirred for a further 2 hours and then added slowly to ice cold water (2000 ml) and methanol (200 ml). After 30 minutes the solid was collected, washed with water, and dried to give the product 24.1 g (100%) m.p. 169°-171° C.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][NH:50][O:51][CH3:52].O>C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[NH:1][CH:2]([C:11](=[O:13])[N:50]([O:51][CH3:52])[CH3:49])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (5.0 g, 17.7 mmol) in methylene chloride (89 ml), BOP reagent (9.39 g, 21.2 mmol), N,O-dimethylhydroxylamine hydrochloride (2.07 g, 21.2 mmol) and TEA (5.92 ml, 42.5 mmol) were added under cooling with ice and stirred for 30 min. The reaction mixture was mixed with water and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (5.76 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=S)[CH:26]=[CH:27][CH:28]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[O:19][C:18]([C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([C:3]5[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[NH:10][C:11]=4[CH:17]=3)=[N:20][N:21]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)c1
Temperature: 4 °C
Reaction time: 1.75 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add 3-chloro phenyl isothiocyanate (69 uL, 0.512 mmol) and stir for 1.75 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 30 min. Allow to stir at room temp overnight. Dilute the reaction with EtOAc (50 mL) and extract with water (10 mL) and 1 N NaOH (10 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Combine the aqueous phases, chill to 4° C., and filter. Combine the solids and suspend them in boiling toluene/EtOAc. Cool the suspension to 4° C. and filter. Wash the solid with Et2O. Dry to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07 (ddd, J=7.96, 2.02, 0.76 Hz, 1H) 7.40 (t, J=8.15 Hz, 1H) 7.50-7.55 (m, 1H) 7.62-7.67 (m, 1H) 7.70 (s, 1H) 7.72 (d, J=2.02 Hz, 1H) 7.75-7.91 (m, 3H) 8.11 (br. s., 1H) 10.99 (br. s., 1H) 13.28 (br. s., 1H); MS m/z=457.9 (M+1).