Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[C:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[NH:18])[NH2:17].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(O)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:16]2[NH:18][C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:17]=2)[CH:20]=1
Reactant: N=C(N)c1cccnc1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc(-c2cccnc2)[nH]1
Temperature: 75 °C
Yield: 50.2 %

Procedure:
ethyl 3-(4-pyridyl)-3-oxopropionate (0.60 g), 3-amidinopyridine hydrochloride (0.54 g) and potassium carbonate (1.15 g) were added to 5 ml of ethanol, and the mixture was heated under reflux at 75° C. for 20 hours. Acetic acid was added to the reaction mixture, and the solvent was removed by distillation. The residue was added with water and then with acetic acid, and the resulting solid was separated by filtration, washed with water and ethyl acetate, and dried to obtain 0.39 g of the desired compound.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[C:10]=1[C:11]([OH:13])=[O:12])(OC(C)(C)C)=[O:2].C(Cl)(=O)C([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][C:15]1[CH:14]=[C:10]2[C:11]([O:13][C:1](=[O:2])[NH:8][C:9]2=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reaction time: 0.17 h

Procedure:
After suspending 2-(Boc)amino-6-chlorobenzoic acid (1.51 g, 5.56 mmol) in toluene (20 mL), the mixture was heated to reflux. Oxalyl chloride (0.572 mL, 6.67 mmol) was added dropwise thereto, and the mixture was vigorously stirred for 10 minutes. After cooling the reaction mixture on ice, the precipitated crystals were filtered out, washed with n-hexane and dried in a desiccator to obtain 5-chloroisatoic anhydride.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:11])[CH3:3].[CH2:12]([O:14][N:15]=[CH:16][CH3:17])[CH3:13].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH2:12]([O:14][N:15]1[CH:16]([CH3:17])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:11])[CH3:13]
Reactant: C=C(C)C1CCCCCC1=O
Reactant: CC=NOCC
Agent: CCON1C(=O)CCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCON1C(=O)CCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cycloheptanone (0.97 g, 6.38 mmol), acetaldehyde O-ethyl oxime (0.66 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.11 g, 73% yield).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[C:14]([C:18]1[O:22][C:21]([CH3:23])=[C:20]([C:24](=O)[CH2:25]Br)[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[O:22][C:21]([CH3:23])=[C:20]([C:24]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:25]=2)[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)CBr
Product: COC(=S)c1cc(-c2nc(-c3cc(C(C)(C)C)oc3C)cs2)c(C)s1
Yield: 66.1 %

Procedure:
Methyl 4-{4-[S-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate: A solution of 955 mg (3.86 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 1 g (3.86 mmol) of 1-[5-(tert-butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one (1 g) in a manner similar to Example 8, step (a) to give methyl 4-{4-[5-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (999 mg, 64%) as a red-brown solid. 1H-NMR (DMSO-d6; 300 MHz) δ 8.14 (s, 1H), 7.74 (s, 1H), 6.46 (s, 1H), 3.86 (s, 3H), 2.74 (s, 3H), 2.66 (s, 3H), 1.27 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C19H21NO3S3, 408.1 (M+H), found 408.0.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28](O)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2].OC1C2N=NNC=2C=CC=1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2]
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCC(=O)O)ccc12
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCC(=O)N3CCN(C)CC3)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of the compound of Example 70 (25 mg, 0.07 mmol) in dichloromethane (3 mL) was added hydroxybenztriazole (10 mg, 0.073 mmol), 1-methylpiperazine (0.008 mL, 0.073 mmol), diisopropylethylamine (0.017 mL, 0.1 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (14 mg, 0.073 mmol). The mixture was stirred at room temperature for 4 days and then quenched with saturated aqueous ammonium chloride solution. After the mixture was diluted with water, it was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated. The title compound was isolated by flash chromatography eluting with a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate. Mass spectrum (m/e) 493 (M++1).
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][Cl:5].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:5].[ClH:5].[CH3:1][N:2]([CH2:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][N:36]1[CH2:35][CH2:34][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])[CH2:38][CH2:37]1.[ClH:5]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1c(-c2ccccc2)oc2c(CN(C)CCCl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCN(C)Cc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Product: Cl
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of 5.2 g of Intermediate XXVII, 3.1 g of 1-(2-methoxyphenyl)-piperazine and 2.2 g of anhydrous potassium carbonate in 50 ml of dimethylformamide was stirred at 70° C. for 7 hours. After cooling to 20°-25° C., the reaction mixture was poured into 500 ml of water, and extracted with dichloromethane. The organic phase was washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate:petroleum ether (98:2). The title compound was obtained by salification with ethanolic hydrogen chloride. m.p. 217°-219° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:73]([NH2:79])[C@H:74]1[O:78][CH2:77][CH2:76][CH2:75]1>C(Cl)Cl.CCOCC>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:79][CH2:73][C@H:74]4[CH2:75][CH2:76][CH2:77][O:78]4)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC[C@@H]1CCCO1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H]1CCCO1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Yield: 71.8 %

Procedure:
13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-N-[[(2S)-tetrahydro-2-furanyl]methyl-7H-indolo[2,1-a[2]benzazepine-10-carboxamide. A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), 1-hydroxybenzotriazole (14 mg, 0.1 mmol), and (S)-(+)-tetrahydrofurfurylamine (10 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. overnight, diluted with CH2Cl2 (5 mL), and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to afford a yellow oil. Et2O (5 mL) was added to dissolve the oil, and concentration afforded the title compound as an off-white solid (32 mg, 72% yield). LC/MS (ESI) retention time: 1.73 min, m/z 637 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.27-1.43 (m, 3 H) 1.47-1.57 (m, 1 H) 1.58-1.70 (m, 2 H) 1.70-1.81 (m, 2 H) 1.86-1.97 (m, 3 H) 1.98-2.12 (m, 4 H) 2.25-2.35 (m, 1 H) 2.42 (s, 3 H) 2.63-2.77 (m, 1 H) 2.78-2.89 (m, 1 H) 3.29-3.46 (m, 1 H) 3.65 (s, 4 H) 3.74-3.85 (m, 2 H) 3.85-3.98 (m, 1 H) 4.09 (ddd, J=14.16, 7.11, 3.40 Hz, 1 H) 4.39 (s, 1 H) 5.08 (s, 1 H) 6.67-6.75 (m, 1 H) 6.82 (s, 1 H) 7.34-7.39 (m, 1 H) 7.40-7.50 (m, 3 H) 7.52-7.59 (m, 1 H) 7.86 (d, J=8.56 Hz, 1 H) 7.99 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3](O)([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=[N:6][OH:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OC)(C)(C)C>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH2:4][C:3]([C:2]([F:26])([F:27])[F:1])([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=3)[O:7][N:6]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C(CC(O)(c2cccc(C(F)(F)F)c2)C(F)(F)F)=NO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1ccc(C2=NOC(c3cccc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
To a solution of 4,4,4-trifluoro-3-hydroxy-1-(4-methylphenyl)-3-[3-(trifluoromethyl)phenyl]butan-1-one oxime (0.45 g) and triphenylphosphine (0.60 g) in tetrahydrofuran (10 mL), diethyl azodicarboxilate (0.44 g) was added, and the mixture was stirred for 24 hours at room temperature. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine and the organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield 3-(4-methylphenyl)-5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[N:24]=[C:23]([O:25][C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28](=[O:36])[N:29]([CH3:35])[CH2:30]4)[C:22]([Cl:37])=[CH:21][N:20]=2)[C:15]([O:38][CH3:39])=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>C1COCC1.C(#N)C.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[N:24]=[C:23]([O:25][C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28](=[O:36])[N:29]([CH3:35])[CH2:30]4)[C:22]([Cl:37])=[CH:21][N:20]=2)[C:15]([O:38][CH3:39])=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cc(C(=O)OCc2ccccc2)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cc(C(=O)O)c(Cl)cc1Nc1ncc(Cl)c(Oc2cccc3c2C(=O)N(C)C3)n1
Reaction time: 2 h

Procedure:
Benzyl 2-chloro-4-[5-chloro-4-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yloxy)-pyrimidin-2-ylamino]-5-methoxy-benzoate (75 mg) is dissolved in THF (150 mL), Pd(OH)2 (0.01 g) is added and the mixture is stirred for 2 h under H2 gas. For working up the mixture is diluted with ACN (20 mL) and Isolute is added. The solvent is filtered off from the catalyst and the solvent is eliminated in vacuo.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.Cl.[NH2:32][CH2:33][C:34]#[N:35].Cl>CN(C=O)C>[F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:35][CH2:34][C:33]#[N:32])[C:4]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: N#CCN
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NCC#N
Temperature: 25 °C

Procedure:
A solution of 3.0 g (0.008 mol) of product of Example 103, 1.72 g (0.017 mol) of triethylamine and 0.79 g (0.008 mol) of aminoacetonitrile hydrochloride in 30 ml of DMF was stirred at 50° C. for 24 hours. The reaction mixture was cooled to room temperature and poured into 3.7% HCl. This solution was extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). The dry ether phase was concentrated in vacuo to 2.56 g of a brown semi-solid oil. The crude product was recrystallized in hexane/ethyl acetate to 0.9 g (28%) of product as a beige solid; mp 87°-89° C.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[CH:18][C:19]([OH:22])=[C:20]([OH:21])[C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>C(O)C.C(O)(=O)C>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[CH:18][C:19]([OH:22])=[C:20]([OH:21])[C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN1CCc2c(ccc(O)c2O)C(c2cccc3ccoc23)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCc2c(ccc(O)c2O)C(c2cccc3c2OCC3)C1

Procedure:
0.5 g (0.0016 mol) 1-(benzofuran-7-yl)-6,7-dihydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in a mixture of 25 ml ethanol and 2 ml acetic acid. 0.2 g catalyst (10% Pd/C) was added and the mixture was submitted to hydrogenation in a Parr apparatus at a pressure of 50 psi. After 24 h the catalyst was filtered off and the solution was concentrated in vacuo. The residue was redissolved in dichloromethane, the solution was washed subsequently with NaHCO3-solution, water and brine. Evaporation in vacuo gave 1-(2,3-dihydrobenzofuran-7-yl)-6,7-dihydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine as an offwhite foam.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:31](=[O:32])[C:30]2[N:29]([CH3:33])[CH:28]=[N:27][C:26]=2[N:25]([CH3:34])[C:23]1=[O:24].C(N(CC)CC)C.Cl>ClCCl>[O:11]=[C:12]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:31](=[O:32])[C:30]2[N:29]([CH3:33])[CH:28]=[N:27][C:26]=2[N:25]([CH3:34])[C:23]1=[O:24]
Reactant: CCCCCCCCCCC(O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
To a solution of oxalyl chloride (0.036 ml, 0.41 mmol) in dichloromethane (3 ml) -78° C. was added dimethylsulfoxide (0.063 ml, 0.82 mmol), and over 5 minutes, 1-(10-hydroxyeicosyl)-3,7-dimethylxanthine (0.135 g, 0.28 mmol) in dichloromethane (2 ml). The reaction was stirred at -78° C. for 30 minutes and after the addition of triethylamine (0.23 ml, 1.64 mmol) allowed to warm to 25° C. over 30 minutes. Hydrochloric acid (1.0M, 10 ml) and dichloromethane (5 ml) were added, the organic phase separated and the aqueous phase washed with dichloromethane (10 ml). The organic portions were combine and dried over magnesium sulfate. Evaporating the solvent left a slightly yellow solid, which upon purification by chromatography (silica, ethyl acetate) produced 0.110 g of 1-(10-oxoeicosyl)-3,7-dimethylxanthine as a white solid (85% yield).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([N:11]([S:22]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[C:27]([CH3:34])[C:26]=1[CH3:35])(=[O:24])=[O:23])[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O[Li].O.Cl>CO.O1CCCC1.O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([CH2:12][N:11]([S:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[C:27]([CH3:34])[C:26]=3[CH3:35])(=[O:24])=[O:23])[C@H:4]([CH2:5][O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:36])=[O:2])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COC(=O)[C@@H](COC(C)(C)C)N(Cc1ccc2[nH]ccc2c1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3[nH]ccc3c2)[C@H](COC(C)(C)C)C(=O)O)c(C)c1C
Temperature: 40 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 2(R)-{(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-[1H-indol-5-ylmethyl]amino}-3-tert-butoxypropionic acid methyl ester (1.0 g, 1.94 mmol) in 50% methanol/tetrahydrofuran (10 mL) was added a solution of LiOH.H2O (160 mg, 3.88 mmol) in water (1 mL). The reaction mixture was heated to 40° C. for 12 h and an additional amount of LiOH.H2O (160 mg, 3.88 mmol) in water (1 mL) was added. After 3 h, the aqueous solution was acidified to pH 3 using 2 N aqueous hydrochloric acid and the product was extracted into ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and concentrated to afford 2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzene-sulfonyl)amino]-3-tert-butoxypropionic acid (0.90 g).
Reaction SMILES: C(OC([N:11]1[C:15]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[C:16]2=[O:33])[C:14](=[O:34])[N:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:12]1=[O:40])=O)C1C=CC=CC=1.C(O)(=O)C.C(O)C>[Pd].COCCOC>[CH2:38]([O:37][C:35]([N:13]1[C:14](=[O:34])[C:15]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[C:16]2=[O:33])[NH:11][C:12]1=[O:40])=[O:36])[CH3:39]
Reactant: CCOC(=O)N1C(=O)N(C(=O)OCc2ccccc2)C2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)N1C(=O)NC2(C1=O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A mixture of 3-benzyloxycarbonyl-1-ethoxycarbonyl-1'-(3,4-dichlorobenzyl)spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.7 g.), 10% w/w palladium on carbon (0.1 g.), acetic acid (0.3 ml.), ethanol (25 ml.) and 1,2-dimethoxyethane (50 ml.) was hydrogenated at atmospheric pressure for 2 hours. The mixture was separated by filtration through diatomaceous earth and the filtrate was evaporated. The residual oil solidified on treatment with a few drops of toluene. The solid obtained was recrystallised from ethyl acetate/petrol 60-80 to give 1-ethoxycarbonyl-1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.7 g.), 176°-179° C.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:7]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][N:21]3[CH2:20][CH2:19][N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH3:10])[CH2:23][CH2:22]3)[CH2:26][CH2:27]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1N1CCN(CC2CCNCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC2CCN(C(=O)C3CCCCC3)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
Cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (0.765 g, 55% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])C.C1COCC1.O.O[Li].O>CO>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:21])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a stirred solution of monoethyl malonate (0.86 g, 0.00649 mole) in DMF (20 mL) was added HOBt (0.795 g, 0.0059 mole) and DMAP (0.790 g, 0.00649 mole). The mixture was cooled to 10° C. and EDCI.HCl (1.7 g, 0.008 mole) followed by biphenyl-4-ylamine (1.0 g, 0.0059 mole) were added and the resulting mixture was stirred at the ambient temperature for overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 1.76 g (94%) of N-biphenyl-4-yl-malonamic acid ethyl ester. To a solution of N-biphenyl-4-yl-malonamic acid ethyl ester (1.7 g, 0.0060 mole) in a mixture of methanol (5 mL), THF (10 mL) and H2O (10 mL) was added LiOH.H2O (0.5 g, 0.012 mole). The reaction mixture was stirred for 2 hours at ambient temperature. The mixture was then concentrated and the residue was diluted with water acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 1.5 g (98%) of N-biphenyl-4-yl-malonamic acid. LC-MS purity: 95.4%, 1H NMR (DMSO-d6): δ 10.3 (s, 1H), 7.7 (m, 6H), 7.4 (t, 2H), 7.32 (t, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:33]([NH:35][C@H:36]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50]C(C)(C)C)=[O:49])=[O:45])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:43])[NH2:42])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28]C(C)(C)C)=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH3:58][C:59]([OH:61])=[O:60].[CH3:62][C:63]([OH:65])=[O:64].CC(O)=O>FC(F)(F)C(O)=O.C(S)C>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:17]([NH:19][C@H:20]([C:33]([NH:35][C@H:36]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([OH:50])=[O:49])=[O:45])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:42])[NH2:43])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[CH3:58][C:59]([OH:61])=[O:60].[CH3:62][C:63]([OH:65])=[O:64]
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCS
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
670 mg of H-Arg-Val-Tyr(tBu)-Arg-Pro-OtBu triacetate are dissolved in a mixture of 10 ml of 90% trifluoroacetic acid and 1 ml of ethyl mercaptan. The solution is left to stand at room temperature for one hour, and is concentrated in vacuo. The residue is partitioned between water and tert.butyl methyl ether. The aqueous phase is stirred with a weakly basic ion exchanger (acetate form) until the pH has become 3.5-4.0. The ion exchanger is filtered off with suction, and the filtrate is freeze-dried.