Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].N1C=CC=CC=1.C1CCCCC1>O1CCOCC1>[Cl:10][C:11]1[C:12]([C:13]([NH:1][C:2]2[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[O:14])=[CH:16][CH:17]=[CH:18][N:19]=1
Reactant: Cc1ccnc(Cl)c1N
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: C1CCCCC1
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Yield: 4.7 %

Procedure:
Using a procedure analogous to that described in Example 1a, the carboxamide was prepared from 12.8 g of 3-amino-2-chloro-4-methyl pyridine, 15.8 g of 2-chloronicotinoyl chloride, 7.1 g of pyridine, 30 ml of cyclohexane and 60 ml of dioxane. After removal of the solvent, the product was dissolved in methylene chloride, washed with water and dried (sodium sulfate). After removal of the solvent, the residue was washed with ethyl acetate to give 1.2 g of the title compound, m.p. 193°-194° C.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:19]=2)=[C:9]1[CH3:38])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:20]2[N:19]=[C:18]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=4)[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:9]=3[CH3:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21]2(=[O:28])=[O:29])=[CH:32][CH:33]=1
Reactant: Cc1c(C2=NN(Cc3ccc(Cl)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3ccc(Cl)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(4-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.15 (d, 1H), 7.91 (t, 1H), 7.82 (t, 1H), 7.45 (m, 6H), 6.89 (dt, 1H), 6.60 (dd, 1H), 5.08 (bs, 2H), 4.59 (s, 2H), 2.08 (s, 3H) ppm. MS calculated for C25H19FClN3O4S—H: 510, observed: 510.
Reaction SMILES: Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35]OC=2)O1.[F-].[K+].ClCCl>CS(C)=O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH3:24])=[C:2]([CH2:33][C:34]#[N:35])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1CC#N
Temperature: 130 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.073 mmol) (Peak1 from Example 167, step 4), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.018 g, 0.095 mmol, from Combi-Blocks Catalog, item # PN-8875), potassium fluoride (13 mg, 0.22 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (12 mg, 0.015 mmol) in dimethyl sulfoxide (0.8 mL)/water (0.3 mL) was degassed with N2 and then stirred at 130° C. for 16 h. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (2.4 mg, 9%). The product was isolated as a single enantiomer. LCMS calculated for C18H20ClN6O (M+H)+: m/z=371.1; Found: 371.1
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.C1(N)C2C(=CC=CC=2)CCC1.ClCCCC(O)=O.Cl[CH2:32][CH2:33][CH2:34][C:35]([NH:37][CH:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1)=[O:36].[H-].[Na+]>C(Cl)Cl.CC#N>[CH:38]1([N:37]2[CH2:32][CH2:33][CH2:34][C:35]2=[O:36])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCCCl)NC1CCCc2ccccc21
Agent: NC1CCCc2ccccc21
Agent: O=C(O)CCCCl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCCN1C1CCCc2ccccc21
Reaction time: 40 h
Yield: 50.2 %

Procedure:
CDI (6.61 g. 40.75 mmoles) and, after 1 hour, 1,2,3,4-tetrahydro-1-naphtylamine (5 g, 33.96 mmoles) were added to 4-chlorobutyric acid (4.16 g, 33.96 mmoles) in CH2Cl2 (200 mL) under stirring. The resulting solution was kept at room temperature for 40 hours, then washed with 1N HCl, NaHCO3 (saturated solution), H2O, NaCl (saturated solution) and dried over anhydrous Na2SO4. The solvent was evaporated and the residue taken up with CHCl3. Upon addition of Et2O under stirring a precipitate was obtained consisting of 4.5 g (17.87 mmoles) of N-(4-chloro-butyroyl)-1,2,3,4,-tetrahydro-1-naphtylamine (silica gel TLC; Eluant EtOAc-Hexane (1:1), RF=0.7) which was dissolved in CH3CN (100 mL). To the mixture, 80% NaH in mineral oil (804 mg, 26.8 mmoles) was added in two portions, the second portion after some hours following the first one. The mixture was then kept at room temperature under stirring for 2 days. The mixture was then filtered, the filtrate evaporated and the residue chromatographed on silica gel using EtOAc-Hexane (1:1) as eluant. 1.93 g of the title compound were obtained. Last step yield=50%, overall yield 26%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([OH:13])=O.[NH2:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].Cl>N1C=CC=CC=1>[C:28]([NH:27][C:22]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([NH:19][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH:21]=1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cc(NC(=O)c2ccccc2)ccc1Cl
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)cc1OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
Phosphoryl chloride (0.074 g) was added to a stirred mixture of 3,4-dimethoxybenzoic acid (0.088 g), N-(3-amino-4-chlorophenyl)benzamide (0.1 g) and pyridine (1 ml) which had been cooled to 0° C. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was poured into 1N aqueous hydrochloric acid solution and the resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried under vacuum at 55° C. There was thus obtained the title compound (0.088 g);
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:8][C:7]=2[CH:31]=1.Cl.N1C=C(CN2C3C=CC=CC=3CN([C:50](C3C4C(=CC=CC=4)C=CC=3)=[O:51])CC2)N=C1>CO>[ClH:1].[ClH:1].[OH:51][CH2:50][C:4]1[CH:3]=[CH:31][C:7]2[CH2:8][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[C:6]=2[CH:5]=1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccccc2C1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Solvent: CO
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2cc(CO)ccc2C1

Procedure:
Example 274 was prepared as an off white solid from Compound B as described for Compound F of Example 41, with chromatography using 5% MeOH/0.5% NH4OH/methylene chloride, and Compound D of Example 1, with purification by prep HPLC before formation of the HCl salt.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[OH:32].[Na+]>Cl>[ClH:1].[CH3:2][C:3]1[N:7]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:13]=2)[N:6]=[CH:5][C:4]=1/[CH:14]=[CH:15]/[CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:32])[NH2:30])[CH:24]=2)[CH2:21][CH2:22]1
Reactant: Cc1c(/C=C/CN2CCN(c3cccc(C#N)c3)CC2)cnn1-c1ncccn1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: Cc1c(/C=C/CN2CCN(c3cccc(C(N)=O)c3)CC2)cnn1-c1ncccn1
Temperature: 25 °C
Reaction time: 62 h

Procedure:
88 mg of the compound obtained in Example 32 (3) was dissolved in 0.5 ml of conc. hydrochloric acid and stirred at room temperature for 62 hours. Then the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform:methanol=100:3). Then the product was converted into hydrochloride with a 1N hydrochloric acid/ethanol solution and recrystallized from ethanol. Thus 50 mg of the title compound was obtained in the form of colorless crystals.
Reaction SMILES: [I-].C[N+]1(C)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>O.CO>[C:11]([N:15]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C[N+]1(C)CCC(=O)CC1
Reactant: CC(C)(C)N
Agent: [I-]
Solvent: CO
Solvent: O
Product: CC(C)(C)N1CCC(=O)CC1
Yield: 4.6 %

Procedure:
A suspension of 64.5 g (253 mmol) of 1,1-dimethyl-4-oxo-piperidinium iodide in 50 mL of water and 90 mL (860 mmol) of tert-butylamine was stirred for 15 min when 1.0 mL of 40% Triton B in MeOH was added. The mixture was refluxed for 2 hr under N2, and then it was extracted with Et2O (4×100 mL). The aqueous phase was basified with 20 g of NaOH in 20 mL of water, and then it was extracted further with Et2O (4×100 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residual oil was shaken with 1.5 L of petroleum ether, which was decanted and concentrated. The residue was distilled under vacuum to provide 1.8 g of 1-tert-butyl-piperid-4-one.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([S:14]C#N)=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(P(CC)CC)C>CC(C)=O.O>[SH:14][C:5]1[CH:4]=[C:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]([OH:1])=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=1
Reactant: N#CSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: CCP(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: Oc1c(-c2ccccc2)cc(S)cc1-c1ccccc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
2'-hydroxy[1,1':3',1"-terphenyl]-5'-yl thiocyanate (32.2 g, 0.106 mole) was dissolved in acetone (150 ml) and water (1.9 ml), stirred and cooled to -5° C. Triethyl phosphine (15.7 ml, 0.106 mole) was added dropwise over a period of 40 minutes. The reaction was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The solvent was evaporated and the product isolated by chromatography on silica.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COc1cc(F)cc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)cc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 100 %

Procedure:
In DMF (20 ml), 5-fluoro-3-methoxy-2-nitrophenol (4.14 g, 22.1 mmol), benzyl bromide (3.2 ml, 26.5 mmol) and potassium carbonate (4.58 g, 33.2 mmol) were stirred at 70° C. for 5 hours. The reaction mixture was poured in water (200 ml), followed by extraction with ethyl acetate (300 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, the title compound (6.13 g, 100%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.[CH3:20][O:21]C(Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([CH:20]=[O:21])=[CH:7][C:6]=3[CH2:5]2)=[CH:13][CH:14]=1
Reactant: COC(Cl)Cl
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)Cc1cc(Br)ccc1-2
Temperature: -2 °C
Reaction time: 0.33 h

Procedure:
To a mechanically stirred solution of commercially available 2-bromofluorene (79.1 g 90% pure, 71.19 g at 100% purity, 0.29 mol) in 350 mL dichloromethane, in a 1-liter 3-neck round-bottomed flask, cooled in a ice-salt bath, tin(IV)chloride (60 mL, 133.56 g, 0.513 mol) was added. Maintaining the temperature at −2° C., over a period of 20 minutes, dichloromethyl methyl ether (33 mL, 41.94 g, 0.365 mol) was added dropwise, stirred near 0 to −1° C. for 1.5 hours, and then allowed to warm to room temperature over a period of 3 hours. The mixture was poured into crushed ice, and methylene chloride was allowed to evaporate. The product slurry was then filtered and washed with water. The dry crude product (mixture of two aldehydes) weighed 87.9 g, m.p. 138-144° C. This was stirred with 750 mL of 10% toluene-heptane at reflux for 2 hours, cooled and filtered at room temperature, 73.5 g, m.p. 161-170° C. This was dissolved in 400 mL hot toluene (hazy solution; tin salts might be still present) diluted with 300 mL heptanes, and the slurry was kept at reflux for 3 hours, cooled and collected at room temperature, 59.0 g, m.p. 176-179° C. A recrystallization by dissolution in toluene (600 mL), clarification while hot, and dilution with heptanes (300 mL) delivered 50 g of pure 7-bromo-9H-fluorene-2-carbaldehyde, m.p. 177-180° C. The yield is 57 or 63% based on assumed purity of 100% or 90% for the sample of 2-bromofluorene used. Mass spec: m/z 272, 274 (M+). Anal Calcd for C14H9BrO: C, 61.57%; H, 3.32%; Br, 29.26%. Found: C, 61.53%; H, 3.44%; Br, 29.22%. 1H NMR (CDCl3), δ ppm: 3.94 (s, 2H), 7.53-7.56 (dd, 1H), 7.68-7.72 (m, 2H), 7.85-7.91 (m, 2H), 8.03 (s, 1H), and 10.04 (s, 1H). 13C NMR: 36.57 (1 sp3C), 120.19, 122.23, 122.46, 125.82, 128.55, 129.81, 130.40, 135.32, 139.21, 143.28, 146.45, 146.72, and 191.90 (13 sp2C).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1.C([O:23]CC)C>>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:23])[C:5]=2[CH:14]=1)#[N:19]
Reactant: CCOCC
Reactant: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from (-)-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained (-)-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1 -benzopyran-4-yl)pyridine N-oxide of melting point 142°-144° C. (from diethyl ether); [α]58920 =76.8° (c=0.997 in ethanol).
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:12]([C:13](O)=[O:14])[O:11][C:10](=[O:16])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)C>[CH2:1]([C@H:8]1[C@@H:12]([CH2:13][OH:14])[O:11][C:10](=[O:16])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)[C@@H](C(=O)O)O1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1N[C@@H](Cc2ccccc2)[C@@H](CO)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.1 g (5 mmol) of (4S,5S)-4-benzyl-oxazolidin-2-one-5-carboxylic acid were dissolved in 15 ml of ethanol. 0.03 ml of sulphuric acid were added and the mixture refluxed for 4 hours. After cooling, 0.04 g of NaOH were addedand the mixture concentrated under a vacuum to 2 g. 4 ml of ethanol were then added and 0.25 g of NaBH4 was added in small portions. Once addition was complete and stirring had been continued for 0.5 hour, the educt was already completely converted. 4 ml of water were added, the mixture neutralised to pH 7 with 1.2 ml of 10% HCl and, after cooling, cooled to 0° C. The solid was separated using a vacuum filter and, due to the small batch size, washed with a disproportionately large quantity of water. The yield after isolation was 0.66 g=63.7%, wherein approximately 0.2 g=20% of theoretical still remained in the mother liquorand washing water. Diastereomer purity was S,S:R,S=98.75:1.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:14][C:15]3[N:16]2[CH:19]=[N:20][N:21]=3)=[CH:11][CH:10]=1)C.[Li+].[OH-].C1COCC1.Cl>O.CO>[C:22]1([C:13]2[C:12]3[C:17](=[CH:18][C:9]([S:8][CH2:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:10][CH:11]=3)[N:16]3[CH:19]=[N:20][N:21]=[C:15]3[CH:14]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1

Procedure:
11d (40 mg, 0.10 mmol) was treated with 1N aqueous LiOH (2 mL) in 3:3:1 THF:MeOH:H2O (2 mL) overnight at room temperature. 1N aqueous HCl was added to adjust to pH 4, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product, 11e.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH3:41])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:37]=[CH:38][CH:39]=[CH:40][C:15]=2[O:14][CH2:13]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][N:11]([CH3:41])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[C:17]2[C:16]2[CH:37]=[CH:38][CH:39]=[CH:40][C:15]=2[O:14][CH2:13]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl(7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in Example 1, Step 6) (0.1 M) in DCM was treated with an excess of TFA (>50 eq.). The mixture was stirred at RT for 1 h. All the volatiles were then removed in vacuo and the residue treated with a solution of HCl/Et2O (2 M) and the resulting mixture concentrated in vacuo. The product was used in the next step without further purification. (ES+) m/z 462 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:19])=[N:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8](Cl)=[CH:7][C:6]=1[CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+].C[Si](C)(C)[O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[NH2:1][C:2]([NH2:19])=[N:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([N:32]2[CH:33]=[CH:34][C:29](=[O:28])[CH:30]=[CH:31]2)=[CH:7][C:6]=1[CH2:16][CH3:17]
Reactant: CCc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reactant: C[Si](C)(C)Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(-n2ccc(=O)cc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
3 g of N-diaminomethylene-2-ethyl-4-chloro-5-methylsulfonylbenzamide [obtainable by reacting methyl 2-methyl-4-chloro-5-methylsulfonylbenzoate with guanidine] are heated with 30 ml of 4-trimethylsilyloxypyridine in the presence of 3 g of K2CO3 in a closed tube at 135° for five hours. The mixture is cooled, the excess silylpyridine is removed by decanting, and the residue is triturated with ether and filtered off with suction. The solid residue is then dissolved in methanol and chromatographed over silica gel (ethyl acetate/methanol). Recrystallization from isopropanol and ethanol gives N-diaminomethylene-2-ethyl-4-(1,4-dihydro-4-oxo-1-pyridyl)-5-methylsulfonylbenzamide, m.p. 261-263°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]2[CH2:18][CH:17]=[CH:16][CH2:15][C:14]2=[O:19])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(C2CC=CCC2=O)cc1OCC
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCCCC2=O)cc1OCC

Procedure:
10.2 g of 2-(3,4-diethoxyphenyl)cyclohex-4-enone in 600 ml of tetrahydrofuran are admixed with 1.5 ml of conc. hydrochloric acid and 400 mg of 10% palladium on carbon and hydrogenated. The catalyst is filtered off, the solution is concentrated under reduced pressure and the residue is chromatographed over silica gel using a mixture of petroleum ether/ethyl acetate in a ratio of 2/1. Concentration of the appropriate eluate fractions gives 8.25 g (80.9% of Th.) of the title compound as an oil which solidifies.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>C(O)C>[CH2:1]([NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)NC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCc1ccccc1)NC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of ethyl 2-(3-benzylureido)-3-phenylpropanoate 13 (2.66 mmol, 0.83 g) and 2 N lithium hydroxide (5.32 mmol, 0.22 g) in ethanol (20 mL) was kept in stirring overnight at room temperature. The reaction was quenched by addition of 2 N HCl until pH=2, afterwards the precipitate was filtered, washed with water (3×30 mL) and dried to obtain the pure 2-(3-benzylureido)-3-phenylpropanoic acid as a pale white solid; 95% yield, m.p. 115-117° C.; recryst. solvent: cyclohexane/benzene; 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 2.85-2.87 (dd, 1H, PhCHHCHCOO), 2.89-2.91 (dd, 1H, PhCHHCOO), 4.38-4.40 (m, 1H, PhCHHCHCOO), 6.14-6.17 (d, 1H, PhCHHNHCONH), 6.54-6.57 (m, 1H, PhCHHNHCONH), 7.18-7.30 (m, 10H, aromatic protons), 12.65 (bs, 1H, COOH); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 36.0, 44.4, 56.8, 125.9, 126.7, 126.9 (2C), 127.7 (2C), 128.5 (2C), 128.6 (2C), 136.6, 137.9, 157.6, 174.7; MS (ESI) m/z: 298.32 [M]+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])([O-:8])=[O:7].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][C:3](=[O:4])[CH2:2][Br:1])([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C(Br)CBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CBr)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Under argon atmosphere bromo-acetyl bromide (2.67 mL, 30.66 mmol) dissolved in DCM (15 mL) was added within 15 min to a mixture of 2,4-dinitro-phenol (5.13 g, 27.88 mmol) and pyridine (2.92 mL, 36.24 mmol) in DCM (40 mL) at 0° C. After 1 h at RT, aqueous citric acid solution (10%, 30 mL) was added to the reaction mixture. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue recrystallized from diethyl ether (75 mL) to afford the title compound.