Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)Cl.[C:6]1([CH2:12][CH2:13][C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)C1C=CC=CC=1.CC(=O)CCC.C1(C=CC(=O)CCC)C=CC=CC=1.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].Cl>C(OCC)(=O)C.[Zn]>[OH:18][C:14]([CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:15][CH2:16][CH3:17])[CH2:47][C:48]([O:50][CH3:51])=[O:49]
Reactant: CCCC(=O)CCc1ccccc1
Reactant: COC(=O)CBr
Agent: CCCC(=O)C=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=Cc1ccccc1
Solvent: CCCC(C)=O
Product: CCCC(O)(CCc1ccccc1)CC(=O)OC
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 5.6 g of zinc powder (85 mmol) in 35 ml of ethyl acetate. After 1.61 ml of trimethylchlorosilane (12.6 mmol) had been added, the mixture was heated at 65° C. for 30 min, then left to cool to 60° C., following which 10 g of neat 1-phenylhexan-3-one prepared by base-catalyzed aldol condensation of benzaldehyde and pentan-2-one and subsequent hydrogenation of the resulting 1-phenylhex-1-en-3-one were added. Subsequently, over the course of 5 min, 10.4 g of methyl bromoacetate (68 mmol) were added dropwise, the temperature being maintained at 65° C. by external cooling. The mixture was stirred for 30 min at 60° C., and following cooling to 0° C., acidified with 35 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration and the organic phase separated. The organic phase was then stirred at 0° C. with 30 ml of 0.5 N hydrochloric acid and finally washed with 20 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was removed by distillation under reduced pressure. Methyl 3-hydroxy-3-(2′-phenylethyl)caproate was obtained in a yield of 13.5 g (95% of theory) and a purity of greater than 97% (HPLC).
Reaction SMILES: [OH:1][CH:2]1[C@@H:7]2[C:8]([CH2:11][OH:12])=[CH:9][CH2:10][C@@H:6]2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][O:3]1>C(Cl)Cl>[CH:11]([C:8]1[C@H:7]2[CH:2]([OH:1])[O:3][CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C@H:6]2[CH2:10][CH:9]=1)=[O:12]
Reactant: COC(=O)C1=COC(O)[C@@H]2C(CO)=CC[C@H]12
Solvent: ClCCl
Product: COC(=O)C1=COC(O)[C@@H]2C(C=O)=CC[C@H]12
Reaction time: 2 h
Yield: 88.6 %

Procedure:
10 g (44.2 mmol) of methyl(4aS,7aS)-1-hydroxy-7-hydroxymethyl-1,4a,5,7a-tetra hydrocyclopenta[c]pyrane-4-carboxylate was dissolved with 600 ml of methylene chloride, and 19.06 g (88.4 mmol) of pyridiniumchlorocromate was added, and stirred for 2 hours. After filtering the reaction mixture, the filtered solution was concentrated and purified by using column chromatography (hexane/ethylacetate=3/1, v/v), and 8.78 g of methyl(4aS,7aS)-7-formyl-1-hydroxy-1,4a,5,7a-tetra hydrocyclopenta[c]pyrane-4-carboxylate was obtained (yield: 89%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[Cl:11].CC(C[AlH]CC(C)C)C.Cl.[OH2:22]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:22])=[CH:5][C:4]=1[Cl:11]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Reactant: O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise DIBAl-H (1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in water (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1>CC(N(C)C)=O>[CH:13]1([N:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CC(N2CCNCC2)C1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCN(C3CCC3)CC2)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 11.3 %

Procedure:
Ethyl 4-fluorobenzoate (0.225 mL, 1.53 mmol) and 1-cyclobutylpiperazine (0.430 g, 3.07 mmol) were taken up in DMA (3 mL) and sealed into a microwave tube. The reaction was heated to 150° C. for 90 mins in the microwave reactor and cooled to room temperature. The reaction was not complete, so it was reheated at 150° C. for a further 1 h. The reaction mixture was evaporated to dryness and the crude product purified by silica column chromatography, eluting with a gradient of 0-2.5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (0.050 g, 11.31%) as a yellow solid.
Reaction SMILES: I.CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[F:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][N:15]2C(=O)O[C:18](=[O:19])[C:17]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:16]23)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C>C(O)C.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:16]3[C:17](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:18](=[O:19])[N:5]3[CH2:6][CH2:7][N:8]=[C:4]23)=[CH:27][CH:28]=1
Reactant: CSC1=NCCN1
Reactant: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2N(Cc2ccc(F)cc2)C2=NCCN12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A charge of 26 kgs. toluene, 2.5 kgs. 2-methylmercaptoimidazoline hydroiodide, 2.4 kgs. N-(p-fluorobenzyl)isatoic anhydride and 1.55 kgs. powdered anhydrous sodium carbonate is refluxed for 18 - 20 hours in a reaction vessel which is vented to a caustic gas washing tower. Any water formed during the reaction is collected in a Dean-Stark separator. The reaction is cooled to 20°C. and 10 kgs. water added. The mixture is stirred for about 30 minutes and the solids collected, washed several times with 2 kg. portions of water, and three times with 0.8 kg. toluene. The solids are then dried at reduced pressure (about 55°C.) to obtain a crude product, m.p. 196°-198°C. The crude is dissolved at 50°C. in a solution of 14 kgs. chloroform and 4 kgs. ethanol and treated in solution with 0.1 kg. decoloring charcoal for about 10 minutes. The charcoal is removed by filtration through a celite bed and solids reprecipitated by concentrating the filtrate to a volume of about 8 liters. This concentrate is cooled to 0°-5°C., the solids collected by filtration, washed with cold ethanol and then diethyl ether, and dried at reduced pressure to obtain 10-(4'-fluorobenzyl)-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 197°-198°C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([CH3:21])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[N:8]1.CI>CCCCCC.O1CCCC1>[CH3:6][C:7]1([CH3:21])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][C:13]=2[CH3:1])=[N:8]1
Reactant: [Li]CCCC
Reactant: CC(C)c1ccc(C2=NC(C)(C)CO2)cc1
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(C)C)ccc1C1=NC(C)(C)CO1
Reaction time: 2 h

Procedure:
n-Butyllithium (52.8 ml of a 2.5M solution in hexane) was added dropwise to a stirred solution of the product of step (i) (27.6 g) in tetrahydrofuran (100 ml) at -20° C. After 2 hours methyl iodide (85.3 g) was added and the mixture was stirred for 2 hours at this temperature then 0.5 hours at room temperature. The reaction mixture was partitioned between brine and ethyl acetate. The aqueous solution was extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5% ethyl acetate in isohexane. Used directly in the next step.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[F-].[Cs+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:11]1[CH:16]=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=[CH:13][N:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Product: Clc1cc(-c2ccccc2)ncn1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
Phenylboronic acid (3.05 g, 25 mmol) was added to a solution of 4,6-dichloropyrimidine (7.45 g, 50 mmol) in 50 mL of dimethoxyethane at 70° C. followed by cesium fluoride (7.60 g, 50.0 mmol). The resulting mixture was stirred for 5 minutes at 80° C. and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.04 g, 2.5 mmol) was then added. The reaction mixture was stirred at 80° C. for one hour then evaporated. The residue was extract with ether (3×50 mL) and EtOAc (1×50 mL). The combined organic layers were washed with 100 mL saturated sodium carbonate solution (100 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography (Biotage 40 L eluting with 250 mL each of 0, 10, 20, 30, 40, 50, 60, 70, 80, and 100% dichloromethane/petroleum ether) to afford 2.20 g, (46.2%) of the product. MS 191.0 (AP+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])[N:5]=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>CC(C)=O>[CH2:23]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[N:6]1[C:2]([CH3:1])=[N:3][N:4]=[N:5]1)[CH3:24]
Reactant: Cc1nnnn1-c1ccccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccccc1-n1nnnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Acetone (3.2 L) and 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid (228 g) were combined then stirred at ambient temperature for 15 minutes. Potassium carbonate (228 g) was added to the reaction mixture in a single portion. Iodoethane (366.8 g) was added dropwise to the reaction mixture producing a slight exotherm. The reaction mixture was heated at reflux for about 4 hours then stirred overnight while cooling to ambient temperature. The precipitated salts were removed by filtration then rinsed with acetone. The combined filtrates were evaporated under vacuum. The residue was dissolved in dichloromethane (1.5 L). The dichloromethane solution was washed with water (1.5 L), dried over magnesium sulfate then concentrated under vacuum to provide 227 g of ethyl-2-(5-methyl-1H-tetrazol-1-yl)benzoate as a white solid m.p. 98-100° C.
Reaction SMILES: [O:1]([NH:19][C:20](=[O:50])[CH2:21][C@@H:22]([N:33]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)=[CH:34]1)[C:23]([NH:25][C@H:26]([CH2:31][OH:32])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:24])[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>C1COCC1>[CH3:28][C:27]([CH3:30])([CH3:29])[C@H:26]([NH:25][C:23](=[O:24])[C@H:22]([N:33]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)=[CH:34]1)[CH2:21][C:20]([NH:19][OH:1])=[O:50])[CH2:31][OH:32]
Reactant: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)NO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)NO)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reaction time: 1.25 h
Yield: 41.6 %

Procedure:
To a solution of N4 -t-butyldiphenylsiloxy-N1 -[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamide (112 mg, 0.160 mmol) in THF (5 mL) was added a solution of tetra-n-butylammonium fluoride (0.20 mL of 1M in THF). After 1.25 hours at ambient temperature, the mixture was added dropwise to 1M pH7 phosphate buffer (40 mL). The resultant precipitate was collected by filtration and washed with H2O. A solution in CH2Cl2 /MeOH was passed through a 0.45μ syringe filter, and the filtrate was concentrated to give a solid which was triturated with EtOH to yield 30 mg (42%) of N1 -[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-N4 -hydroxy-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamide as an amorphous solid, which decomposed >200° C. 1H NMR (CD3COOD): δ 8.91 (d, 2H, J=6.6 Hz), 8.23 (d, 2H, J=7.0 Hz), 7.93 (d, 2H, J=8.8 Hz), 7.76 (d, 2H, J=8.5 Hz), 7.42 (s, 1H), 6.95 (s, 1h), 6.60 (s, 1H), 5.44 (t, 1H, J=7.4 Hz), 3.92-3.88 (m, 2H), 3.63-3.55 (m, 1H), 3.21 (dd, 1H, J=6.4, 14.5 Hz), 3.03 (dd, 1H, J=8.1, 15.1 Hz), 0.93 (s, 9H). Anal: Calculated for C25H30N4O4.0.4 H2O: C, 66.08; H, 6.96; N, 11.95. Found: C, 65.92; H, 6.79; N, 11.86.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].C(OC(=O)C)C.O>C1COCC1>[CH2:10]([O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2ccccc2)nc1
Temperature: 0 °C

Procedure:
20 mmol of 6-Chloro-nicotinonitrile were dissolved in THF. 1.1 eq. of benzyl alcohol were added. The reaction mixture was cooled to 0° C. and flushed with argon. 4 eq of NaH were added slowly. After 15 min the product was isolated via extraction from ethylacetate/water.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:9][C:10]12[CH:19]=[CH:18][CH2:17][CH2:16][CH:15]1[C:14](=[O:20])[O:13][C:11]2=[O:12]>>[CH3:9][C:10]1([CH:19]=[CH:18][CH2:17][CH2:16][CH:15]1[C:14]([OH:13])=[O:20])[C:11]([OH:7])=[O:12].[CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7]
Reactant: CC12C=CCCC1C(=O)OC2=O
Agent: OCCCCCCO
Product: CC1(C(=O)O)C=CCCC1C(=O)O
Reaction time: 2 h

Procedure:
The same type of separable flask as used in Example 29 was charged with 118g (1 mol) of 1,6-hexanediol and 332g (2 mols) of methyltetrahydrophthalic anhydride. Addition reaction was carried out 2 hours at 140° to 170° C, providing 442g of 2:1 adduct of methyltetrahydrophthalic acid-1,6-hexanediol having an acid value of 238.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[N:15]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(Cc2ccccc2)c2ccccc2Br)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.30 mmol) was dissolved in dry N,N-dimethylformamide (5.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 63.6 mg, 1.59 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C. benzyl bromide (0.267 g, 1.56 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 1 day. The reaction mixture was then added into an excess of water-ice and a gum formed. The gum was filtered by suction, washed with water and dried to yield a crude solid. The crude solid was purified via flash chromatography (30% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][CH:7]([OH:31])[C:6]=2[CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
7-Chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (3.2 g, 7.1 mM) is suspended in methanol (27 mL), and thereto is added at one time crystalline sodium borohydride (96 mg=2.5 mM), and the mixture is reacted for about one hours. To the reaction mixture is added dropwise 0.5% diluted hydrochloric acid (9.3 mL), and the mixture is stirred at room temperature and then cooled. The precipitated crystals are separated by filtration, and dried at room temperature to give the desired 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (2.97 g) as white powder (Yield 92%, Mp 224.5-225.5° C.).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ccc(Br)c(F)n1
Reaction time: 15 h
Yield: 22.6 %

Procedure:
To a solution of 6-fluoro-2-pyridylamine (1.0 g, 8.93 mmol) in chloroform (55 mL) was added N-bromosuccinimide (1.59 g, 8.93 mmol). The solution was stirred in the dark for 15 hours, at which time it was added to CH2Cl2 (200 mL) and 1N NaOH (50 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (50 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (25% EtOAc/hexanes) yielding 5-bromo-6-fluoro-2-pyridylamine (386 mg, 22%). LCMS (m/z): 190.9/192.9 (MH+); 1H NMR (CDCl3): δ 7.59 (t, J=8.7 Hz, 1H), 6.25 (dd, J=8.1, 1.2 Hz, 1H), 4.58 (bs, 1H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([NH:15][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of benzenesulfonyl chloride in anhydrous CH2Cl2 (0.5M solution) cooled to 0° C. under N2 was added t-butylamine (2.2 equiv) slowly through a dropping funnel. After completion of addition, the reaction was stirred at toom temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was extracted into ether and washed with 2N NaOH, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled product, which was used directly in the next step.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]1([S:12](Cl)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[C:1]([NH:5][S:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
To a cooled (0° C.) solution of tert-butylamine (42.9 mL, 410.6 mmol) in THF (840 mL) was added dropwise benzenesulfonyl chloride (26.2 mL, 205 mmol) and the reaction mixture was stirred at room temperature under an argon atmosphere for 6 h. The mixture was then filtered and the collected solid washed with THF. The filtrate was concentrated, redissolved in CH2Cl2 and washed with 0.1N HCl and H2O. The organic solution was dried and concentrated to afford the desired product (41.8 g, 95%).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:28]([O:27][C:25]([N:22]1[C:21]2[CH:32]=[CH:33][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:34])[C:20]=2[N:24]=[CH:23]1)=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: Cc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (DPT) (14.3 g) and 4dimethylaminopyridine (0.1 g) in CH2Cl2 (500 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole (7.82 g) in CH2Cl2 (250 mL). The mixture is stirred for 15 minutes at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=2[F:15])[CH2:3][CH2:2]1>[C].[Pd].C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=2[F:15])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(OCC2CC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(OCC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of 1-(cyclopropylmethoxy)-2-fluoro-4-nitrobenzene (3.00 g), 10% palladium-carbon (containing water (50%), 3.00 g) and THF (30 mL) was stirred at room temperature for 1 hr under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure to give the title compound (2.57 g).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[N:7]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.C(O)C.CN(C=O)C>[N:7]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([O:11][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88 %

Procedure:
The solution of 33 mg (0.10 mmol) of Cs2CO3 in 0.1 ml of distilled water was added to the solution of 43 mg (0.20 mmol) Boc-Pro-OH in 2 ml of anhydrous ethanol. The mixture was stirred at room temperature for 40 min and then evaporated to dryness. The residue was dried over anhydrous CaCl2 to provide a colorless powder which was dissolved in 1 ml of DMF. To the DMF solution 34 mg (0.2 mmol) of benzyl bromide was added slowly. The mixture was stirred at 50° C. for 16 hr and the formed precipitates of CsBr were filteled. The filtrate was evaporated to dry. The residue was dissolved in 20 ml of ethyl acetate and the solution was washed with saturated solution of NaHCO3, NaCl and 5% solution of KHSO4 successively. The organic phase was separated and dried over anhydrous NaSO4. After filtration the filtrate was evaporated at 37° C. to provide 54 mg (88%) of the title compound as a colorless syrupy.