Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][C:11](=O)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].CN.[BH3-][C:19]#[N:20].[Na+].[ClH:22].[CH3:23][OH:24]>>[ClH:1].[CH3:19][NH:20][CH:11]1[CH2:12][CH:13]2[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)([CH2:14]2)[CH2:10]1.[ClH:22].[CH2:23]([O:24][CH2:2][CH3:7])[CH3:19]
Reactant: CO
Reactant: [BH3-]C#N
Reactant: O=C1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Agent: CN
Agent: Cl
Agent: [Na+]
Product: CCOCC
Product: CNC1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one (100 mg; 0.41 mmol) in methanol (3 mL) was added methylamine (33% in ethanol; 1 mL) and NaCNBH3 (33 mg; 0.53 mmol; 1.3 eq). The mixture was stirred at room temperature overnight. The reaction mixture was cooled to 10° C., and acidified with 1 N HCl (4 mL). The reaction mixture was concentrated at 30° C., and the resulting aqueous layer was diluted with H2O (10 mL). The aqueous layer was then extracted with ethyl acetate (15 mL) to remove nonpolar impurities. The aqueous layer was then adjusted to pH 9 with 1N NaOH, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to an oily residue. The oil was then dissolved in diethyl ether (5 mL), and the HCl salt was formed by slowly adding HCl/diethyl ether solution (0.5 mL). The slurry was stirred for 30 minutes before filtration. The solids were rinsed with diethyl ether (5 mL) and the compound was quickly transferred to a vacuum dessicator and dried under vacuum for 12 hours to give the title compound as a beige solid (76 mg; 64%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.78-0.93 (m, 1 H) 1.19-1.27 (m, 1 H) 1.44-1.50 (m, 1H) 1.67-1.80 (m, 1H) 2.03-2.13 (m, 1 H) 2.35-2.50 (m, 3 H) 2.55-2.73 (m, 7 H) 3.11-3.35 (m, 1 H) 3.74-3.88 (m, 1 H) 7.16 (dd, 1 H) 7.23-7.41 (m, 2 H). 13C NMR (100 MHz, CHLOROFORM-d) δ ppm 17.41 (s, 1 C) 24.68 (s, 1 C) 26.81 (s, 1 C) 27.02 (s, 1 C) 30.08 (s, 1 C) 31.31 (s, 1 C) 32.24 (s, 1 C) 32.58 (s, 1C) 33.62 (s, 1C) 35.90 (s, 1C) 38.455 (s, 1C) 59.96 (s, 1 C) 63.08 (s, 1 C) 126.08 (s, 1 C) 128.75 (s, 1 C) 130.53 (s, 1 C) 132.59 (s, 1 C) 143.92 (s, 1 C). MS (M+1) 256.0, HPLC Purity 99% (AUC).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>>[CH3:21][CH:22]1[NH:23][CH2:24][CH2:25][N:26]([C:2]2[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:27]1
Reactant: COc1ccccc1OCC(C)Oc1nccnc1Cl
Reactant: CC1CNCCN1
Product: COc1ccccc1OCC(C)Oc1nccnc1N1CCNC(C)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51 mmol) and 2-methylpiperazine (260 mg, 2.6 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 118 mg (65%) of the title product. HRMS m/z calcd for C19H26N4O3 (M)+ 358.2005, found 358.2018. Anal. (C19H26N4O3) C, H, N.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[O:4]=[C:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.Cl>O1CCCC1.C(OCC)(=O)C.N1C=CC=CC=1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([CH:6]([C:5](=[O:4])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:25])=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Cc1ccccc1)C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a suspensin of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and the mixture was cooled to 0° C., then pyridine (2.5 ml) was added. The mixture was stirred at 20° C. for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for 2 hours, the mixure was partitoned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.CI.[C:14](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][N:1]1[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CCNCC1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction solution was concentrated under reduced pressure, and water (150 mL) was added thereto, followed by extracting with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. To the residue (2.64 g) was added 1 N aqueous solution of sodium hydroxide (20 mL), and stirred at room temperature overnight. To the reaction solution was added 1 N hydrochloric acid (20 mL) to neutralize, and concentrated under reduced pressure. To the residue was added ethanol, and the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. After repeating this operation again, to the residue were added ethanol and ethyl acetate to crystallize, which gave 1-methylpiperidine-4-carboxylic acid as colorless solid (1.79 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:36]3[CH2:37][C:34]([F:38])([F:33])[CH2:35]3)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC1(F)CNC1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](CN1CC(F)(F)C1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol; Example 210, Step A) in 1,2-dichloroethane (3 mL) was added 3,3-difluoroazetidine hydrochloride (55.7 mg, 0.430 mmol) followed by sodium triacetoxyborohydride (91 mg, 0.430 mmol). After stirring overnight, the mixture was quenched with water. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes). Fractions containing the product were transferred to a separatory funnel and sat. aq. NaHCO3 and dichloromethane were added. The aqueous layer was back extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17]C(N)=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.IC.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O.[CH3:42][N:43]([CH:45]=O)[CH3:44]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:14]=[CH:15][C:45]([N:43]([CH3:42])[CH3:44])=[CH:17][CH:18]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
(2R)-2-[N-(4-Chlorobenzene-sulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoic acid amide (Example 48, 0.10 g, 0.22 mmol) was dissolved in DMF (5 mL). To this solution was added iodomethane (62 mg, 0.44 mmol), and cesium carbonate (220 mg, 0.66 mmol). The reaction was then stirred at 40° C. for 18 h. The reaction was poured into EtOAc and water. The organic was collected, dried over MgSO4, and concentrated to an oily residue. The residue was further purified (Biotage 40S, loaded in CH2Cl2, eluted in 25% EtOAc/hexanes) to yield a yellow powder (15 mg, 16%). MS (ESI), (M+H)+ 438.1; 1H NMR (DMSO-d6, 500 MHz) δ 7.74 (dd, 2H, J=1.9, 6.7), 7.54 (dd, 2H, J=1.9, 6.8), 7.43 (s, 1H), 7.16 (d, 2H, J=8.6), 7.01 (s, 1H), 6.61 (d, 2H, J=8.8), 4.59 (q, 2H, J=16, 25), 4.34 (dd, 1H, J=5.0, 9.3), 2.85 (s, 6H), 1.27-1.47 (m, 3H), 0.80 (d, 3H, J=5.9), 0.52 (d, 3H, J=6.1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([OH:10])[C:3]=1[N+:11]([O-])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([OH:10])[C:3]=1[NH:11][C:14](=[O:16])[CH3:15]
Reactant: COc1cc(O)c([N+](=O)[O-])c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Product: COc1cc(O)c(NC(C)=O)c(O)c1
Yield: 67.3 %

Procedure:
2,6-Dihydroxy-4-methoxynitrobenzene (0.60 g, 3.24 mmol) was hydrogenated in the presence of acetic anhydride (0.29 g, 4.86 mmol) and 10% Pd/C (0.2 g) in methanol (30 mL) under atmospheric pressure and room temperature. The catalyst was removed by filtration through a pad of celite and the the crude product was purified by flash chromatography (SiO2, Toluene-ethyl acetate, 3:3 then 1:2) to afford the subtitle compound (0.43 g, 67.9%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:5])[CH3:4].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Cl)([O-:8])=[O:7].[OH-:16].[Na+]>CS(C)=O>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([O:1][CH2:2][CH:3]([O:5][C:12]2[CH:13]=[CH:14][C:9]([N+:6]([O-:7])=[O:16])=[CH:10][CH:11]=2)[CH3:4])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [OH-]
Reactant: CC(O)CO
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(COc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
76 g (1 mol) 1,2-dihydroxypropane, 346.5 g (2.2 mols) nitrochlorobenzene and 140 g powdered sodium hydroxide were reacted following the procedure described in Example 1 in 600 ml DMSO.
Reaction SMILES: C([O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6])C.[CH3:11][N:12]([CH2:14][CH2:15][CH2:16][N:17]=[C:18]=[S:19])[CH3:13].[CH2:20]([N:22](CC)CC)[CH3:21]>CO>[NH2:6][C@H:5]([C:4]([OH:10])=[O:3])[CH:7]([CH3:9])[CH3:8].[CH3:11][N:12]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][C:20](=[O:3])[NH:22][C:18]1=[S:19])[CH3:13]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: CN(C)CCCN=C=S
Solvent: CO
Product: CC(C)[C@H](N)C(=O)O
Product: CN(C)CCCN1CC(=O)NC1=S

Procedure:
Valine ethyl ester (0.01 mol) in 30 ml of anhydrous methanol was reacted with dimethylaminopropyl isothiocyanate (0.01 mol) for 3 hours at 50° C. The solution was made basic by the addition of two equivalents of triethylamine. Solvent was removed by rotary evaporation. Water was added to the solid residue and the residue was filtered and washed with water. The residue was dissolved in methanol and analyzed by FAB/MS. The expected product, dimethylaminopropyl thiohydantoin valine (MH+=244), was obtained.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:1][CH:2]2[CH2:3][O:21]2)=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCNC(=O)c1ccc(Cl)s1
Solvent: ClCCl
Product: O=C(NCC1CO1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An ice-cooled solution of 2.0 g (9.92 mmol) of N-allyl-5-chloro-2-thiophenecarboxamide in 10 ml of dichloromethane is admixed with metachloroperbenzoic acid (3.83 g, about 60% strength). The mixture is stirred overnight, during which it is allowed to warm to room temperature, and is then washed with 10% sodium hydrogen sulphate solution (three times). The organic phase is washed with saturated sodium bicarbonate solution (twice) and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The product is purified by silica gel chromatography (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[F:7])(=O)[CH3:2].[CH2:9]1C[O:12][CH2:11][CH2:10]1.C(OCC(Br)F)(=[O:16])C.C(=O)CC.C1COCC1.C(=O)CC.C(OC(C)C)(C)C>O>[F:7][CH:6]([CH:11]([OH:12])[CH2:10][CH3:9])[C:5]([O:4][CH2:1][CH3:2])=[O:16]
Reactant: C1CCOC1
Reactant: CC(=O)OCC(F)Br
Solvent: CCC=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(F)C(O)CC
Reaction time: 0.33 h
Yield: 85 %

Procedure:
After a 500 mL reaction vessel which had been sufficiently dried inside by vacuum heating was replaced with dry nitrogen, and placed in an ice bath, 24.2 g (370 mmol/1.5 equivalent) of activated metal zinc and 300 mL of THF (dehydrated) were added into the reaction vessel. Thereto was added a bromofluoroethyl acetate/THF solution (46.91 g (253.6 mmol/1.0 equivalent) of bromofluoroethyl acetate and 80 mL of THF (dehydrated)) dropwise over 5 min. After the dropwise addition, the temperature of the mixture was elevated to the room temperature, followed by stirring for 20 min. Thereto was added a propionaldehyde/THF solution (17.76 g (305.8 mmol/1.2 equivalent) of propionaldehyde and 80 mL of THF (dehydrated)), and the mixture was stirred for 60 min at a room temperature. Thereafter, water and diisopropyl ether were added thereto, and two-layer separation was carried out. The organic layer thus obtained was washed with diluted hydrochloric acid and water, and the moisture was eliminated using anhydrous magnesium sulfate, followed by filtration. Then diisopropyl ether was distilled off to give 35.4 g (yield: 85%) of ethyl 2-fluoro-3-hydroxy-pentanoate represented by the following formula.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@H:3]([O:17][CH3:18])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][C@@H:3]([O:17][CH3:18])[C:2]([F:1])([F:19])[F:20])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:23][CH:24]=1
Reactant: CO[C@H](CN1CCc2ccc(N)cc2CC1)C(F)(F)F
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(C[C@@H](OC)C(F)(F)F)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-((R)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from 3-((R)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 335. Product isolated as a yellow solid (56 mg, 24%). LCMS (m/e) 567 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 8.08 (s, 1H), 7.36-7.25 (m, 3H), 7.19-7.11 (m, 2H), 6.91 (d, 1H, J=7.9 Hz), 6.87 (s, 1H), 6.13-6.05 (m, 1H), 3.75-3.65 (m, 1H), 3.61 (s, 3H), 2.93 (d, 3H, J=4.8 Hz), 2.89-2.65 (m, 10H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:6][C:7]1[CH:8]=[C:9]([C:12]([OH:2])=[O:13])[S:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: O=Cc1cc(Br)cs1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Chromium(VI) oxide (20 g), and concentrated sulfuric acid (32 g) were dissolved in water (50 mL) and when dissolution was complete, the volume was made up to 100 mL with water. 55 mL of the resulting solution was added dropwise to a solution of 4-bromothiophene-2-carboxaldehyde (19.1 g) in acetone (200 mL) stirred at 0° C. After 2 h, the solution was diluted with water and extracted with chloroform. The organic extracts were washed with water, then extracted with aqueous sodium hydroxide. The alkaline mixture was acidified by cautious addition of concentrated hydrochloric acid then extracted with chloroform. The organic layer was then dried(Mg2SO4), filtered, and evaporated. The resulting solid was recrystallised from diethyl ether/hexane to give a colourless solid; MS (ES+) 207, 209 (MH+).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH:26]C(=O)[C@@H](N(C2C=CC=CC=2)C(N)=S)CC2C=CC=CC=2)[C:9]1=[O:47])=[O:6])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH:10]([NH2:26])[C:9]1=[O:47])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)[C@H](Cc1ccccc1)N(C(N)=S)c1ccccc1)CN2c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2c1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
(−)-1-tert-Butylcarbonylmethyl-2-oxo-3-[(2S)-[2-(N-phenylthioureido)-3-phenylpropionyl]amino]-5-phenyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.50 g) was dissolved in trifluoroacetic acid (30 ml), the solution was stirred at 50° C. for one hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (50 ml), concentrated hydrochloric acid (20 ml) was added, and refluxed for one hour. The resultant mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=20:1), to thereby obtain 1.40 g of the titled compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:20]=O>O>[OH:14][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[OH:13])[CH2:20][NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6]2
Reactant: C=O
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Reaction time: 8 h

Procedure:
(S)-2-Amino-3-(3,4-dihydroxy-phenyl)-propionic acid (90 g) was suspended in 0.8 L water, then 18.2 mL concentrated sulfuric acid in 0.5 L additional water was added with stirring. Formaldehyde solution (136 mL, 37 wt %) was then added while stirring and the mixture was stirred 18 hours at rt. It was quenched by addition of 24.4 g NaOH in 0.5 L water, dropwise over 1 h while cooling. The resulting mixture was stored overnight at 4° C., and the solid that formed was collected by filtration, washed with hot water (70° C.), cooled again and collected by filtration. The solid was treated with 0.5 L MeOH and evaporated, then stored under vacuum overnight to give 65 g desired product. 1H NMR (400 MHz, MeOH-d4): 6.64(s, 1H), 6.59(s, 1H), 4.29-4.21(m, 3H), 3.29-3.21(m, 1H), 3.11-3.01(m, 1H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12](=[O:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=1)C>C1COCC1.C1CCCCC1>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12](=[O:27])[CH2:2][C:1]#[N:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCCCN(C)C)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(CC(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
The [4-(3-Dimethylamino-propxy)-phenyl]-acetic acid ethyl ester is then condensed with the lithium anion of acetonitrile by the following method: A solution of dry acetonitrile (0.627 mL) in 20 mL of THF, that had been cooled in a dry ice-acetone bath for 2 h under Ar(g), is treated dropwise with 6 mL of a 2M solution of n-butyl lithium in cyclohexane. This mixture is allowed to stir at −78° C. for an additional 1.5 h, and is subsequently treated with 2.45 gms. of [4-(3-dimethylamino-propoxy)-phenyl]-acetic acid ethyl ester in dropwise fashion. The resulting solution is allowed to stir at −78° C. for an additional 30 minutes, and is then allowed to warm to room temperature overnight. The reaction mixture is then vacuum filtered affording the desired nitrile, 4-[4-(3-dimethylamino-propoxy)-phenyl]-3-oxo-butyronitrile, as a white solid (20-28% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[N:12]=1
Reactant: COc1ccc2c(=O)[nH]c(-c3ccc(OC(C)C)cc3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(OC(C)C)cc3)cc2c1
Yield: 67.4 %

Procedure:
A solution of 3-(4-isopropoxyphenyl)-6-methoxyisoquinolin-1(2H)-one (3.5 g, 11.31 mmol) in POCl3 (11 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (2.5 g, 67.4%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.06-8.04 (d, J=8 Hz, 1H), 8.03-8.01 (d, J=8 Hz, 2H), 7.81 (s, 1H), 7.22-7.20 (d, J=8 Hz, 1H), 7.00 (s, 1H), 6.99-6.97 (d, J=8 Hz, 1H), 4.63 (m, 1H), 3.96 (s, 3H), 1.38 (m, 6H).