Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:44][C@@H:45]([CH3:48])[CH2:46][OH:47]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:44][C@@H:45]([CH3:48])[CH2:46][OH:47])=[O:14])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: C[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a cooled (0° C.) solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 1) (0.80 g, 1.77 mmol) in DMA (3.2 mL) was added isobutyl chloroformate (0.28 mL, 2.13 mmol) and 4-methylmorpholine (0.25 mL, 2.30 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added (S)-(+)-2-amino-1-propanol (0.21 mL, 2.66 mmol) and DMAP (0.02 g, 0.18 mmol). Stirred at ambient temperature overnight. Purified crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=509) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a pale yellow foam (0.61 g, 67%).
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:20]([OH:23])(=[O:22])=[O:21].Cl.C[O-].[Na+:27]>C(Cl)(Cl)Cl>[S:20]([O-:23])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])=[O:21].[Na+:27]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCC(C)CCCCCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methylhexadecanol (124 g, 0.484 mol), prepared as an intermediate in Example I. Chlorosulfonic acid (60 g, 0.509 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot ethanol (55° C., 2 L). The mixture is vacuum filtered immediately. The filtrate is concentrated to a slurry on a rotary evaporator, cooled and then poured into 2 L of ethyl ether. The mixture is chilled to 5° C., at which point crystallization occurs, and vacuum filtered. The crystals are dried in a vacuum oven at 50° C. for 3 hrs. to obtain a white solid (136 g, 92% active by cat SO3 titration).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.C(OC(C)C)(C)C.[C:30]1([CH2:36][O:37][C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:36]([O:37][C:38](=[O:39])[NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:4]([CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:5]=2)[CH:9]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COC(OC)c1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.14 mol), prepared as in Example 65, and diisopropyl ether (0.16 mol) in DCM (1000 mL) was cooled to 10° C., and carbonochloridic acid phenylmethyl ester (also known as benzyl chloroformate) (0.16 mol) was added dropwise, then the reaction mixture was stirred overnight at room temperature and washed with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (eluent: 100% CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][C@@H:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[C:18]=3[CH:17]=[CH:16]2)[C@H:12]([OH:34])[C@@H:11]1[OH:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:36](N1C=CN=C1)(N1C=CN=C1)=[S:37]>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[C@@H:11]2[C@@H:12]([O:34][C:36](=[S:37])[O:35]2)[C@H:13]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][C@@H:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[C:18]=3[CH:17]=[CH:16]2)[CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@@H]2OC(=S)O[C@H]12
Temperature: 80 °C
Yield: 81.3 %

Procedure:
To a solution of (1S,2R,3S,5R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentane-1,2-diol (179 mg, 0.362 mmol) in DMF (2.00 mL) under an atmosphere of nitrogen was added 1,1′-thiocarbonyldiimidazole (72.3 mg, 0.406 mmol) and the solution was heated to 80° C. for 3 h. The solvent was removed and the residue was purified by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the title compound (158 mg, 81%). LC/MS: Rt=2.24 min, ES+ 538 (FA standard).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:19]I>O1CCCC1.O>[CH3:19][C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CI
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)c2ccccc2Oc2ccccc21
Reaction time: 0.17 h

Procedure:
9.61 g (0.04 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 150 mL of tetrahydrofuran, combined with a solution of 5.0 g (0.042 mol) potassium lert-butoxide in THF, and stirred for 10 minutes. 5 mL (0.08 mol) of methyl iodide are then added dropwise with gentle cooling; after all has been added, the mixture is stirred for 1 hour at ambient temperature. The reaction mixture is diluted with water to a total volume of 800 mL, extracted with diethyl ether, and the organic phase is extracted with saturated, aqueous Na2CO3 solution, washed with water, dried over magnesium sulfate, and the solvent is distilled off. The product is purified by recrystallization from methanol. Yield: 6.05 g of white crystals (70% of theoretical yield); melting point: 91° C.-92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:4]=1.C1C(=O)N([I:36])C(=O)C1>C(#N)C>[I:36][C:4]1[C:5]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)=[N:6][C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I

Procedure:
Compound 20 (113 mg, 0.287 mmol) was dissolved in acetonitrile (3 mL) and NIS (129 mg, 0.574 mmol) was added. The solution was heated to reflux for 1 h. The solvent was evaporated and the residue dissolved in EtOAc, washed with sat. NaHCO3, NaS2O3, water, and brine. The organics were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a colorless foam. 1H NMR (CDCl3) δ 5.07 (d, J=6.8 Hz, 1H), 3.99 (br s, 1H), 3.88 (s, 3H), 3.86-3.73 (m, 8H), 3.43 (br s, 3H), 1.90-1.86 (m, 1H), 1.70-1.63 (m, 2H), 1.56-1.55 (m, 1H), 1.42 (s, 9H); LCMS 2.95 min, 520 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](Br)[C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:15]([Sn](CC)(CC)CC)[CH3:16]>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([CH2:15][CH3:16])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC[Sn](CC)(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N
Yield: 52.5 %

Procedure:
A solution of 2,4-dinitro-6-bromoaniline (1.6 g, 6.1 mmol), tetraethyltin (2.4 ml, 12.2 mmol) and Cl2Pd(PPh3)2 (100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reaction mixture was concentrated in vacuc, yielding an oil which was purified on silica gel column chromatography (CH2Cl2, neat) to provide 0.68 g (3.2 mmol, 33%) of 2,4-dinitro-6-ethylaniline, which was converted to the diamine (0.45 g, 95%) on hydrogenation (H2/Pd—C).
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15](I)[CH:14]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[CH:21]#[C:22][CH2:23][CH2:24][OH:25].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:18]=[CH:17][C:16]4[O:19][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][C:15]=4[CH:14]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1I
Reactant: C#CCCO
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Temperature: 65 °C

Procedure:
4-(6,7-Dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-2-iodo-phenol (440 mg, 1.17 mmol), homopropargyl alcohol (147.3 mg, 2.1 mmol) and triethyl amine (295 mg, 2.92 mmol) were dissolved in DMF (15 ml). To this solution was added copper (I) iodide (66.3 mg, 0.34 mmol) and bis-triphenylphosphine palladium (II) chloride (81.9 mg, 0.117 mmol). The reaction was flushed with nitrogen and heated at 65° C. for 12 hours. Solvent was removed under reduced pressure and the residue purified on silica gel (10%-75% EtOAc in hexane) to give 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzofuran-2-yl]-ethanol.
Reaction SMILES: CN(C)[C:3]1(OC)[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=1.C(O)(C)C>C1C=CC=CC=1>[C:18]([C:17](=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8])[C:16]1[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=1)#[N:19]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: COC1(N(C)C)CCCN1C
Solvent: c1ccccc1
Solvent: CC(C)O
Product: CN1CCCC1=C(C#N)c1ccc(Cl)cc1
Yield: 23.1 %

Procedure:
Stir 7.9 g of the title compound of Example 85 and 7.05 g of 4-chlorobenzylcyanide in 30 ml of benzene for 3 hours at 45°. Free the resulting reaction mixture from solvent by distillation to produce a dark-brown crystalline residue. Take up this residue with 10 ml of isopropanol and filter it to obtain 2.5 g of the title compound as yellowish crystals of m.p. 68° to 71°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([NH:20][C:21]3([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([NH:29][C:30]([NH2:32])=[NH:31])=[N:9][CH:8]=1.Cl>>[ClH:6].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([NH:20][C:21]3([C:26]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([NH:29][C:30]([NH2:32])=[NH:31])=[N:9][CH:8]=1
Reactant: COCCN
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)Cl)CCCC3)cc12
Agent: Cl
Product: COCCNC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Yield: 28 %

Procedure:
1-[({4-Chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-N-(2-methoxyethyl)cyclopentanecarboxamide hydrochloride ##STR87## 1-[({4-Chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-N-(2-methoxyethyl)cyclopentanecarboxamide was prepared from 2-methoxyethylamine and 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclopentanecarbonyl chloride, following the same procedure described in example 76. This product was treated with ethereal HCl (1N) and the mixture evaporated in vacuo. The residual solid was dissolved in EtOH, water (1 drop) added, the solution concentrated in vacuo until precipitation occured, and the resulting solid filtered, washed with Et2O, and dried under vacuum, at 50° C., to afford 1-[({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-N-(2-methoxyethyl)cyclopentanecarboxamide hydrochloride (35 mg, 28%).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(CO)cc1
Temperature: 25 °C

Procedure:
Mix 4-dimethylaminobenzaldehyde (3.3 g, 22 mmol), sodium borohydride (830mg, 22 mmol) and absolute ethanol (25 mL). Stir at room temperature until the reaction is complete, pour onto dilute hydrochloric acid and extract into ethyl acetate. Separate the organic phase and extract the aqueous phase with ethyl acetate (2×). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography to give 4-(dimethylamino)benzyl alcohol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C.[C:27]([CH2:31][CH2:32][C:33](Cl)=[O:34])([O:29][CH3:30])=[O:28]>C(Cl)Cl>[C:27]([CH2:31][CH2:32][C:33]([NH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:34])([O:29][CH3:30])=[O:28]
Reactant: NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCC(=O)NCc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.1 %

Procedure:
To a solution of 400 mg (1.54 mmol) of 3-aminomethyl-2,5-dithienylpyrrole (XVIII) and 378 ul (3.07 mmol) of diisopropylethylamine in 15 ml of anhydrous methylene chloride was added 3-carbomethoxypropionyl chloride (1.6 ml, 9.23 mmol). After stirring for 5 minutes at room temperature, the reaction mixture was quenched by the addition of 1 ml of water. The aqueous layer was extracted three times with 5 ml portions of chloroform and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude reaction product was chromatographed on 100 g of silica gel. Elution with chloroform:methanol, 95:5, gave 456 mg (39%) of the amide (XXVI) as a greenish solid having a mp of 48°-49° C., and Rf :0.55 (chloroform:methanol, 98:2).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].O[CH2:27][CH:28]1CC1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]3[CH2:28][CH2:27]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: CN1Cc2c(C(=O)OCC3CC3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
A mixture of 5.0 g (15.6 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 20 ml of hydroxymethyl-cyclopropane and 0.5 g of powdered potassium cyanide is heated to 130° for 18 hours, about 1 ml of solvent being distilled off after 1.3 hours and after 6 hours. The mixture is subseqently evaporated in vacuo and the residue is partitioned between chloroform and water. The chloroform phase is washed three times with water, dried over magnesium sulphate and evaporated. The material obtained is chromatographed on silica gel while eluting with ethyl acetate and subsequently crystallized from ethyl acetate. There is obtained cyclopropylmethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 194°-195°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([CH3:22])[C:10](=[O:21])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:11][C:10](=[O:21])[C:9]=1[CH3:22]
Reactant: CC(C(=O)CC(=O)c1ccccc1F)C(=O)c1ccccc1Cl
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2Cl)n(-c2ccccc2)c(-c2ccccc2F)cc1=O
Yield: 25.1 %

Procedure:
In 450 ml of xylene were suspended 15.3 g of 1-(2-chlorophenyl)-2-methyl-5-(2-fluoro-phenyl)-1,3,5-pentanetrione, 6.4 g of aniline, 6.6 g of para-toluenesulfonic acid and 85 g of Molecular Sieves 5A, followed by refluxing the resultant mixture for 8 hours. Xylene was distilled off from the reaction mixture and 300 ml of chloroform was added to the residue. The mixture obtained was filtered and the filtrate was washed first with 10% hydrochloric acid and then with a 10% aqueous solution of sodium hydroxide. After washing the chloroform phase further with water, the solution in chloroform was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate-n-hexane, 1:3) to afford crude crystals. The crystals were recrystallized from ethyl acetate, yielding 4.5 g of 2-(2-chlorophenyl)-6-(2-fluorophenyl)-3-methyl-1-phenyl-4(1H)-pyridinone having a melting point of 182°-183° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.[OH-].[Na+]>C(Cl)Cl>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23]([NH:10][C@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)C(N)CO
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N[C@H](CO)C(C)C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Diisopropylethyl amine (17.4 ml, 134 mmol) was added a solution of (DL)-valinol (9.85 g, 95 mmol) in methylene chloride (100 ml). The reaction mixture was cooled to 0° C., treated with a solution of p-toluoyl chloride (12.8 ml, 91 mmol ) in methylene chloride (50 ml) and then allowed to warm to room temperature. After stirring for 3 hours, excess aqueous sodium hydroxide solution was added and the reaction was transferred to a separatory funnel. The organic layer was separated and the aqueous layer washed with one portion of methylene chloride. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. Chromatography eluting with 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes gave N-p-toluoyl valinol (18.04 g).
Reaction SMILES: [Cl:1][CH:2](Cl)[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[CH2:13]([Mg]Br)[CH2:14][CH3:15]>O1CCCC1>[Cl:1][CH:2]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCC[Mg]Br
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Solvent: C1CCOC1
Product: CCCC(Cl)B1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
0.5 g (2.37 mmol) of 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was dissolved in 10 ml of tetrahydrofuran and the solution was cooled under a nitrogen atmosphere to -78° C. 2.4 ml (2.4 mmol) of 1M propylmagnesium bromide were added dropwise and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ethyl acetate, saturated sodium chloride solution and 2M hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulphate. After evaporation there was obtained 0.38 g of 2-[1(RS)-chlorobutyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as an oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[C:33](=O)([O:37]CC)[O:34][CH2:35][CH3:36]>O>[CH2:35]([O:34][C:33]([CH2:2][C:1]([O:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:7][CH:6]=1)=[O:3])=[O:37])[CH3:36]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(C)=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)CC(=O)OCC)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
The product from (b) (42 g, 0.12 mol) was added portionwise to a suspension of potassium t-butoxide (21.3 g, 0.19 mol) in diethyl carbonate (56.6 g, 0.48 mol) at 75° C. over 10 minutes. Heating was continued at 95° C. for 1 h. After cooling to 50° C., the suspension was poured into cold water (1 liter) and extracted with ethyl acetate (3×400 ml). The organic solution was dried and evaporated under reduced pressure to give the product (47 g, 93%) as a yellow waxy solid which was used in the next reaction without further purification.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>CCOCC>[O:3]=[C:2]([CH3:4])[CH:1]=[N:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CC(=O)C=O
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(N=CC(C)=O)CC1
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 2.67 mL, 3.15 g, 17.5 mmol) in 50 mL of Et2O at room temperature was added dropwise ethyl 4-amino-piperidinecarboxylate (3.0 mL, 3.01 g, 17.5 mmol). After 20 min, the solution was diluted with 50 mL of Et2O and washed with 3×30 mL of water. The solution was concentrated in vacuo to yield 2.3 g (58%) of the imine product which was used as such in the subsequent step: 1H NMR (CDCl3) δ 7.58 (1H, s), 4.07 (2H, q, J=7.1 Hz)), 4.04 (2H, m), 3.39 (1H, m), 3.02 (2H, m), 2.31 (3H, s), 1.65 (4H, m), 1.19 (3H, t, J=7.1 Hz).