Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([O:51][CH2:52][C@H:53]2[C@H:57]([CH2:58]OS(C3C=CC(C)=CC=3)(=O)=O)[O:56][C:55]([CH3:71])([CH3:70])[O:54]2)(=[O:50])=[O:49])=[CH:44][CH:43]=1>CN(C=O)C.[Cl-].[Na+].O>[C:30]([O:29][C:27]([NH:26][C@@H:7]([CH2:8][CH2:9][CH:10]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:58][C@H:57]2[C@H:53]([CH2:52][O:51][S:48]([C:45]3[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=3)(=[O:50])=[O:49])[O:54][C:55]([CH3:70])([CH3:71])[O:56]2)=[CH:23][CH:24]=1)[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:34])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2OC(C)(C)O[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2OC(C)(C)O[C@H]2COc2ccc(CC(CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)cc1
Yield: 53.1 %

Procedure:
500 mg (1.04 mmol) (2S)-2-tert.-Butoxycarbonylamino-5-(4-hydroxy-benzyl)-hexanedioic acid di-tert.-butyl ester, 144 mg (1.04 mmol) potassium carbonate and 491 mg (1.04 mmol) [(4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl]bis(methylene) bis(4-methylbenzenesulfonate) in 12 mL DMF were heated in a microwave at 100° C. for 2 h. Brine (300 mL) was added and the mixture was extracted with dichloromethane (3×100 mL). The combined organic fractions were dried over sodium sulfate and concentracted. The crude product was purified by Flash chromatography (Silica, 2-40% ethyl acetate in hexane) to afford 430 mg (52%) di-tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(4-{[(4S,5S)-2,2-dimethyl-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-dioxolan-4-yl]methoxy}benzyl)hexanedioate.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:30]3[CH:31]=[CH:32][C:33]4[C:37]([CH:38]=3)=[N:36][N:35]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:34]=4)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:39]([N:35]1[CH:34]=[C:33]2[C:37]([CH:38]=[C:30]([C:8]3[CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:31]=[CH:32]2)=[N:36]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.8 %

Procedure:
To a suspension of tert-butyl 4-{4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]phenyl}piperazine-1-carboxylate (610 mg, 1.02 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at rt for 17 h. The mixture was evaporated to dryness and saturated, aqueous NaHCO3 was added to the residue. The resulting solid was collected by filtration and was dried in vacuo to afford 489 mg (96%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.99-7.91 (m, 3 H), 7.81 (d, 1 H), 7.65 (s, 1 H), 7.41-7.25 (m, 5 H), 7.19 (d, 1 H), 7.06-6.96 (m, 3 H), 5.65 (s, 2 H), 3.14 (s, 4 H), 2.89 (s, 4 H); ES-MS m/z 501.4 [M+H]+, HPLC RT (min) 2.25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][C:11]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:10]1[C:32]([O:34][CH3:35])=[O:33].[CH3:36]N1CCNCC1.C=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][C:11]([C:27](=[CH2:36])[C:28](=[O:29])[O:30][CH3:31])=[C:10]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: CN1CCNCC1
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2)N1
Agent: C=O
Solvent: CC(=O)O
Product: C=C(C(=O)OC)C1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
Dimethyl 4-(2,6-dichlorophenyl)-2-methoxycarbonylmethyl-6-[2-(phenyl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate (588 mg, 1.135 m mol) and N-methylpiperazine (0.132 ml, 1.19 m mol) were dissolved in acetic acid (3 ml) and to the solution was added paraformaldehyde. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and partitioned between CH2Cl2 (50 ml) and aqueous NaHCO3 solution (20 ml). The aqueous layer was extracted with CH2Cl2 (30 ml). The combined organic layer and the extract were washed with brine (10 ml), dried (MgSO4), and concentrated in vacuo to give a yellow oil. This was crystallized from ethyl acetate and isopropyl ether gave a yellow solid (270 mg, 50.9%). Second crop was obtained from the mother liquid (78 mg, 14.7%). 1H NMR (D2O) δ7.35-7.16 (m, 7H), 7-05-6.97 (m, 1H), 6.21 (br.s, 1H), 6.06 (s, 1H), 5.52 (br.s, 1H), 5.43 (br.s, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 3.46 (s, 3H), 3.10-2.80 (m, 4H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C1(C)C=CC=CC=1.[CH3:19][CH2:20][O:21]C(C)=O>>[C:20]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])(=[O:21])[CH3:19]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=O)c2ccccc21

Procedure:
T.L.C. (PhCH3 /AcOEt=75/25): slightly impure for isatin.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][NH:14][CH3:15]>C1COCC1>[OH:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][C:10]([N:14]([CH3:15])[CH3:13])=[O:11]
Reactant: CNC
Reactant: O=C1CCC(c2ccccc2)O1
Solvent: C1CCOC1
Product: CN(C)C(=O)CCC(O)c1ccccc1

Procedure:
A solution of γ-phenyl-γ-butyrolactone (4.84 g, 29.8 mmol) in 200 ml of a 2 molar solution of dimethylamine in THF was stirred under a nitrogen atmosphere at room temperature for 2 days. The solvent was removed under reduced pressure to give 6.26 g of 4-hydroxy-N,N-dimethyl-4-phenyl-butyramide as a light brown oil, MS [M+H]+ m/e 208.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][C@H:17]([NH:25][C:26](=[O:30])[C:27](O)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]([NH:25][C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][OH:15])=[O:30]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C(=O)N[C@@H](CO)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.210 g; 0.890 mmol), (R)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid (0.219 g; 0.979 mmol), HATU (0.339 g: 0.890 mmol) and N,N-diisopropylethylamine (0.389 mL; 2.23 mmol) in DMF (5 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in dichloromethane, the organic layer was washed with water and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.226 g (63%) of (R)-N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(1-hydroxy-3-phenylpropan-2-yl)oxalamide as a white solid.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:17][C:14]2[S:15][C:16]3[C:8]([CH:6]4[CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:7]4)=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=3[N:13]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 4-chloromethyl-benzoic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as light brown powder. MS: m/e=434(M+H+).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]([Mg]Br)=[CH2:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][N:19]3[C:28]=2[CH:27]=[C:26]2[C:21]([CH3:30])([C:22](=[O:29])[CH2:23][CH2:24][CH2:25]2)[CH2:20]3)=[CH:12][CH:11]=1.[OH-].[NH4+].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[CH:18][N:19]3[C:28]=2[CH:27]=[C:26]2[C:5]([CH3:6])([C:22]([CH:21]=[CH2:30])([OH:29])[CH2:23][CH2:24][CH2:25]2)[CH2:20]3)=[CH:14][CH:15]=1
Reactant: CC12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCCC2=O
Reactant: C=C[Mg]Br
Agent: O=C([O-])O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC1(O)CCCC2=Cc3c(-c4ccc(F)cc4)ncn3CC21C
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To anhydrous cerium(III) chloride (274 mg, 1.1 mmol) was added anhydrous THF (4 mL) under nitrogen. The mixture was stirred at RT for 30 min before vinylmagnesium bromide (1.1 mL, 1.1 mmol) was added dropwise at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 30 min before a solution of 1-(4-fluorophenyl)-5a-methyl-5,5a,8,9-tetrahydroimidazo[1,5-b]isoquinolin-6(7H)-one (step a, 66 mg, 0.22 mmol) in anhydrous THF (2 mL) was added dropwise at the same temperature. The reaction mixture was stirred at −78° C. for 30 min and at RT for 1 hr. Concentrated aqueous ammonium hydroxide (1.5 mL) was added. The solid was filtered off through a celite pad and washed with ethyl acetate (3×2 mL). The organic filtrate was dried (Na2SO4), concentrated under reduced pressure, and dissolved in methanol (2 mL). Purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 1-(4-fluorophenyl)-5a-methyl-6-vinyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-ol (40 mg, 0.12 mmol, 55% yield) as a glassy solid (after neutralization using saturated aqueous sodium bicarbonate solution and extraction with ethyl acetate). MS found: (M+H)+=325.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:19](O)[CH2:20][OH:21].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][C:5]2([O:21][CH2:20][CH2:19][O:8]2)[CH2:4][CH:3]1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: CC1(C)CCC(=O)CC1S(=O)(=O)c1ccccc1
Reactant: OCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1(C)CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Yield: 84 %

Procedure:
To a solution obtained by dissolving 4.4 g of 4,4-dimethyl-3-(phenylsulfonyl) -cyclohexan-1-one in 45 ml of benzene, were added 1.1 nm of 1,2-ethanediol and 0.3 g of anhydrous paratoluenesulfonic acid. The resulting mixture was heated under ref lux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, followed by recrystallization from ethyl ether, whereby 4,4-dimethyl-1,1-(ethylenedioxy)-3-(phenylsulfonyl)-cyclohexane was obtained in the form of white crystals. Yield: 84%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([O:16][C:17]([N:19]([CH3:23])[CH2:20][CH2:21]O)=[O:18])([CH3:15])([CH3:14])[CH3:13].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:12]([O:16][C:17]([N:19]([CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:23])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCN(C)C(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 72.3 %

Procedure:
Methyl 3-hydroxybenzoate (6.4 g, 42 mmol), alcohol 121a (7.4 g, 42 mmol), diisopropyl azodicarboxylate (8.3 mL, 42 mmol), and triphenylphosphine (11.1 g, 42 mmol) were stirred in dry THF (120 mL) at 0° C. for 1 h, then for 18 h at room temperature. After evaporation of solvent, the product was isolated by chromatography on silica gel, eluting with 0% to 30% EtOAc in hexane to yield a clear oil (9.4 g). IR(film) cm-1 1726, 1696. 1H NMR(300 MHz, CDCl3): 7.64-7.09 (m, 4H), 4.13 (m, 2H), 3.92 (s, 3H), 3.62 (br, 2H), 2.99 (s, 3H), 1.46 (s, 9H). Anal. Cald'd for C16H23NO5 : C, 62.11; H, 7.51; N, 4.53; Found: C, 61.67; H, 7.43; N, 4.47. HR-MS: Calc'd. 310.1654, Found 310. 1650.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:5]=2[N:4]=1)[CH3:2].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:27]([O:26][C:24]([CH2:23][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2])=[O:25])[CH3:28]
Reactant: CCc1nc2c(OCc3ccc(OC)cc3)cccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(CC)nc2c(OCc3ccc(OC)cc3)cccc21
Yield: 66.6 %

Procedure:
A solution of 2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole (282 mg), ethyl bromoacetate (184 mg) and potassium carbonate (414 mg) in dimethylformamide (3 ml) was stirred for 2 hours, and to the reaction mixture were added ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate:n-hexane =1:2 to 2:1, v/v) to give 1-ethoxycarbonylmethyl-2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole (245 mg) as white powder.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:30]=[C:29]([CH3:31])[O:28][N:27]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(N)no1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 70.7 mg, 0.25 mmol) in oxalyl chloride (215 μL, 2.46 mmol) was cooled to 0° C. and then treated with 1 drop of dry N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 30 min and then stirred at 25° C. for 3 h. The reaction mixture was concentrated in vacuo to afford a yellow oil. This yellow oil was dissolved in a small amount of methylene chloride and then slowly added to a solution of 3-amino-5-methylisoxazole (48.3 mg, 0.49 mmol) and triethylamine (68 mL, 0.49 mmol) in methylene chloride (1.2 mL). The resulting reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with ethyl acetate (100 mL) and then washed with a 10% aqueous hydrochloric acid solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionamide (78.3 mg, 87%) as a yellow glass: mp 84–86° C.; FAB-HRMS m/e calcd for C18H20Cl2N2O2 (M+H)+ 367.0981, found 367.0982.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[CH3:33][NH:34][CH3:35]>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:34]([CH3:35])[CH3:33])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: CNC
Product: CN(C)c1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2-chloropyridine-3-carboxamide and 10 ml of 40% N,N-dimethylamine gives 700 mg of the desired product :M+ =451.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C)[CH3:9])=[CH:4][C:3]=1[OH:18].OC1C=C(C(C)(CCCCCCC)C)C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:9])=[CH:4][C:3]=1[OH:18]
Reactant: CCCCCCCC(C)(C)c1ccc(Br)c(O)c1
Agent: CCCCCCCC(C)(C)c1cccc(O)c1
Product: CCCCCCC(C)(C)c1ccc(Br)c(O)c1

Procedure:
In like manner, 2-(4-bromo-3-hydroxyphenyl)-2-methylnonane is prepared in 82% (8.5 g.) yield as an oil from 7.8 g. (0.033 mol.) of 2-(3-hydroxyphenyl)-2-methylnonane:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:16])[CH:9]=[C:10]([O:14]C)[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[C:4]([CH3:17])[C:3]=1[N+:18]([O-:20])=[O:19].B(Br)(Br)Br.C([O-])(O)=O.[Na+].[K+].[Br-]>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[C:8](=[O:16])[CH:9]=[C:10]([OH:14])[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[C:4]([CH3:17])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1cc(=O)c2c(C)c([N+](=O)[O-])c(C)cc2[nH]c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cc2[nH]c(=O)c(O)cc(=O)c2c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6,8-dimethyl-3-methoxy-7-nitro-1H-1-benzazepine-2,5-dione (460 mg, 1.66 mmol) in dry CH2Cl2 (50 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CHICl2 (6 mL, 1M, Aldrich) in one portion over 2 min at rt. The reaction suspension immediately became orange. The reaction was allowed to stir under N2 at rt for 60 min. The reaction was added to saturated NaHCO3 (60 mL) and the resulting mixture was vigorously stirred for 15 min. An orange aqueous portion and an organic emulsion were present. The mixture was vacuum filtered and the collected solid washed with CH2Cl2 (3×5 mL). The aqueous portion was washed with CH2Cl2 (1×10 mL). Analysis TLC, 20% dioxane, 57% 2-propanol, 11.5% H20, 11.5 % NH4OH) showed the solid and aqueous portions to be identical. Therefore, they were combined and the resulting suspension acidified (pH 2) with coned HCl. The resulting suspension was allowed to stir for 10 min at rt and the solid collected by filtration. The collected solid was washed to neutrality with H2O (6×2 mL). Crystallization from 95% EtOH (dissolved in boiling solvent (15 mL), hot filtered, concd to 7 mL, allowed to cool to rt) yielded a beige crystalline solid (186 mg, 43%, pure by 1H NMR and TLC); mp 229.5-230.5 (dec); 1H NMR (DMSO-d6) δ2.17 (s, 3H), 2.23 (s, 3H), 6.34 (s, 1H), 7.23 (s, 1H), 10.72 (s, 1H), 11.40 (s, 1H); IR (KBr) 3208 (m), 3091 (w), 3061 (w), 3003 (w), 1672 (m), 1646 (s), 1616 (s), 1572 (m), 1532 (m), 1443 (w), 1398 (m), 1364 (m), 1350 (m), 1320 (m), 1271 (m), 1219 (m), 883 (m), 862 (w), 815 (w), 785 (w), 727 (w), 682 (w), 636 (w), 601 (w), 565 (w), 520 (w), 458 (m); Anal. Calcd for C12H10NO5 : C, 54.97; H, 3.84; N, 10.68. Found: C, 54.89; H, 3.70; N, 10.65.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)=[O:30]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([F:39])[CH:38]=2)=[O:30])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1cc(F)cc(F)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cc(F)cc(F)c1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 3,5-difluorobenzyl chloroformate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[NH:16])[NH:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.Cl>O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:16][C:22](=[O:23])[O:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=N)NO)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2noc(=O)[nH]2)C1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Crude (R)-3-(N-hydroxycarbamimidoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (887 mg, 3.86 mmol) and CDI (94 mg, 5.8 mmol) were dissolved in dioxane (30 mL) and heated to reflux. After 1 h, the reaction was concentrated in vacuo. The crude reaction mixture was dissolved in CH2Cl2 and the pH was adjusted to 3 by adding 1M HCl to the solution. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to yield 872 mg of crude (R)-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11](=[O:19])[CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH:16]1([CH2:15][N:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]2=[O:19])[CH2:17][CH2:18]1
Reactant: O=c1cc(OCc2ccccc2)ccn1CC1CC1
Agent: [Pd]
Solvent: CCO
Product: O=c1cc(O)ccn1CC1CC1
Yield: 100.5 %

Procedure:
A mixture of intermediate D1 (2.0 g, 7.83 mmol) and a catalytic amount of 10% palladium on activated carbon in ethanol (300 ml) was stirred under a hydrogen atmosphere for two hours. The mixture was filtered through diatomaceous earth and the solvent was evaporated in vacuo to yield intermediate D2 (1.3 g, 100%) that was used without further purification.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C@H:5]1[CH2:10][O:9][CH2:8][C@@H:7]([C:11]([OH:13])=[O:12])[CH2:6]1>C(OCC)C.CO>[OH:4][C@H:5]1[CH2:10][O:9][CH2:8][C@@H:7]([C:11]([O:13][CH3:3])=[O:12])[CH2:6]1
Reactant: O=C(O)[C@@H]1COC[C@H](O)C1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1COC[C@H](O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of diazomethane in diethyl ether (approx. 0.4 M) is added in excess to a solution of 23 mmol of (cis)-5-hydroxytetrahydropyran-3-carboxylic acid in 300 ml of methanol at 0° C. The mixture is stirred at 0° C. for 2 hours and then quenched with magnesium sulphate, filtered and evaporated. The crude title compound is identified by means of the Rf.