Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:21]([O-])=O)[C:14]=1[S:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[Cl-].[NH4+].C>C(O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:21])[C:14]=1[S:15][CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN(C)CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)CCSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Temperature: 60 °C
Reaction time: 20 h
Yield: 107 %

Procedure:
A 50 ml round-bottom flask with a magnetic stirrer was charged with [2-(6-chloro-8-nitro-9H-β-carbolin-7-ylsulfanyl)-ethyl]-dimethyl-amine (106 mg, 0.30 mmol) in 8 ml of anhydrous ethanol. To the resulting orange mixture at RT was added 0.33 M aqueous ammonium chloride (1.95 ml, 0.64 mmol) and iron powder (540 mg, 9.67 mmol). The reaction mixture was heated to 60° C. and stirred vigorously for 20 hr. Next, the mixture was cooled to RT, diluted with ethyl acetate (20 ml) and activated charcoal (ca. 150 mg) was added. The resulting mixture was filtered through a pad of celite and the resulting filtrate concentrated to afford 103 mg of 6-chloro-7-(2-dimethylamino-ethylsulfanyl)-9H-β-carbolin-8-ylamine as a yellow solid. The crude product was used directly in the coupling step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N+:22]([O-])=O)[C:16]=1[OH:25])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=1[OH:25])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 91.1 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-[2-(tert-butoxycarbonylamino)ethyl]-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (200 mg, 0.51 mmol) was reduced with hydrogen and 10% Pd/C (100 mg) to form the desired product (170 mg, 92%). 1H NMR (MeOD-d4): δ 6.84 (m, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 1.42 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[C:13]([Cl:20])[C:14]4[N:15]([CH:17]=[CH:18][N:19]=4)[CH:16]=[C:11]3[NH:10]C2=O)=[C:4]([Cl:22])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:33]1([S:36](N)(=[O:38])=[O:37])[CH2:35][CH2:34]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:12]2[C:11]([NH:10][S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])=[CH:16][N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13]=2[Cl:20])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=c1[nH]c2cn3ccnc3c(Cl)c2n1-c1ccc(Br)cc1Cl
Reactant: NS(=O)(=O)C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the crude product (Step J) in 3 ml anhydrous THF was added LHMDS (0.4 ml, 0.4 mmol, 1M/THF) at 0° C. and the mixture was stirred for 5 min. The cyclopropyl sulfonamide (83 mg, 0.59 mol) was added neat and the mixture was warmed to room temperature and stirred for 15 h. The mixture was quenched with brine, diluted with H2O and extracted using a mixture of EtOAc/THF (3:1). The organic phase was washed with brine and dried with Na2SO4. Subsequent column chromatography (100% EtOAc) gave the title product as a brown oil (36 mg, 20% over the 2 last steps). Rf (100% EtOAc)=0.35. 1H-NMR (500 MHz, MeOH-D3): δ=8.80 (s, 1H), 7.89 (s, 1H), 7.86-7.85 (d, 1H), 7.68-7.66 (dd, 1H), 7.60-7.58 (d, 1H), 7.46 (s, 1H), 1.51-1.37 (m, 2H), 1.23-1.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[NH:9]2)=[CH:4][CH:3]=1.Cl[C:27]1[CH:28]=[C:29]([CH3:37])[C:30]2[N:31]([C:33]([CH3:36])=[N:34][N:35]=2)[N:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[N:9]2[C:27]2[CH:28]=[C:29]([CH3:37])[C:30]3[N:31]([C:33]([CH3:36])=[N:34][N:35]=3)[N:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nn2c(C)nnc12
Reactant: COc1ncccc1-n1nc(C)c2c1C(=O)NC2c1ccc(Cl)cc1
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(C)c3nnc(C)n3n1)C2c1ccc(Cl)cc1

Procedure:
The title product was prepared in analogy to the procedure described in Example 110 using 4-(4-chlorophenyl)-1-(2-methoxypyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 71.4) and 6-chloro-3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (Step 111.2). The crude material was first purified by silica gel column chromatography (CH2Cl2/MeOH 1-5%), followed by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 9-14% in 6 min_total 11 min). tR: 4.71 min (HPLC 1); tR: 1.10 min (LC-MS 2); ESI-MS: 501 [M+H]+ (LC-MS 2); Rf=0.44 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 2.51-2.57 (m, 6H) 3.92 (s, 3H) 6.61 (s, 1H) 7.20 (dd, J=7.8, 5.1 Hz, 1H) 7.37-7.44 (m, 2H) 7.47-7.54 (m, 2H) 7.97-8.06 (m, 2H) 8.32 (d, J=4.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]([Cl:18])=[C:13]([Cl:17])[C:14]([OH:16])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:31])[CH3:21]>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1([C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:22]([CH2:20][CH3:21])[C:23]=3[CH3:31])[O:19][C:14](=[O:16])[C:13]([Cl:17])=[C:12]1[Cl:18])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCn1c(C)cc2ccccc21
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(Cl)=C(Cl)C(=O)O
Product: CCn1c(C)c(C2(c3c(C)[nH]c4ccccc34)OC(=O)C(Cl)=C2Cl)c2ccccc21

Procedure:
Following a procedure similar to that described above in Example 25, part B, 5.0 g (0.017 mole) of 4-(2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 2.7 g (0.017 mole) of 1-ethyl-2-methylindole were interacted to obtain 5-(2-methyl-3-indolyl)-5-(1-ethyl-2-methyl-3-indolyl)3,4-dichloro-2(5H)-furanone (Formula V: R=Y=Y1 =H; R1 =R3 =CH3 ; R2 =CH3CH2) as a red-blue solid which melted in the range of 282°-285° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:9]([OH:11])=O)[C:4](=[O:16])[CH:3]=1.[NH2:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:9]([NH:17][C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[CH:20][CH:19]=2)=[O:11])[C:4](=[O:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(CC1CC1)n1ccc(Br)cc1=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(Br)cc2=O)cc1

Procedure:
290 mg (purity 94%, 0.95 mmol) of 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 114 mg (purity 80%, 21% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>CN(C=O)C>[F:33][C:34]([F:43])([F:44])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:2]=2[NH2:1])=[CH:37][CH:36]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Nc1c(O)cccc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
2-amino-3-hydroxybenzoic acid (2 g, 13 mmol) was dissolved in 20 ml of DMF and at 0° C. EDCI (2.7 g, 1.2 equiv.), hydroxybenzotriazole (1.9 g, 1.2 equiv.) and 4-trifluoromethylbenzylamine (2 ml, 1.2 equiv.) were added. The mixture was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from EtOAc/ether gave 3.5 g of a beige solid. Yield=86% 1HNMR (DMSO, 200 MHz) δ 4.49 (2H, d, J=5.6 Hz), 6.00 (2H, bs), 6.41 (1H, t, J=8 Hz), 6.76 (1H, d, J=7.6 Hz), 7.11 (1H, d, J=8.2 Hz), 7.51 (2H, d, J=8 Hz), 7.69 (2H, d, J=8 Hz), 8.81 (1H, bt), 9.58 (1H, bs); [M+1] 311.1 (C15H13F3N2O2 requires 310.27).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=O)[CH:15]=[CH:14][N:13]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)=[N:20][N:21]=[C:9]1[SH:10]
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC(=O)c1ccnc(Cl)c1
Solvent: CN(C)C=O
Product: Sc1nnc(-c2ccnc(Cl)c2)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 571 %

Procedure:
A mixture of 1-chloro-2-isothiocyanatobenzene 1 (0.4 g, 2.33 mmol) and 2-chloropyridine-4-carbohydrazide 11 (0.4 g, 2.33 mmol) in DMF was stirred at ambient temperature for 18 hours, concentrated to dryness, and 20 mL of 10% K2CO3 (aq.) was added. The resulting mixture was stirred under reflux for 6 hours. The clear solution was cooled to ambient temperature, washed with ether, and acidified with 1N HCl. The solid was collected, washed with H2O and ether, and dried to afford compound 13 (4.3 g). Yield: 86%.
Reaction SMILES: [C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:29])([OH:28])[OH:27])[P:22](=[O:25])([OH:24])[OH:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-]CC.[Na+:33].C(O)C>O1CCCC1>[C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[C:21]([P:26](=[O:27])([O-:28])[O-:29])[P:22](=[O:23])([O-:24])[O-:25])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:33].[Na+:33].[Na+:33].[Na+:33]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(O)O)P(=O)(O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)([O-])[O-])P(=O)([O-])[O-]
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
[2-[2-(1-Tridecynyl)phenyl]ethenylidene]bisphosphonic acid (0.102 g, 0.23 mmol) prepared according to Example 10 was dissolved in dry tetrahydrofuran (10 ml) and stirred while sodium ethoxide in ethanol (0,177M, 5.19 ml, 0.92 mmol) was added. After 20 minutes, the solvent was removed under reduced pressure to give a light solid. The solid was powdered and washed with dry ethanol, then dried under vacuum, 40.8 mg, 0.084 mmol, 36.5% yield; mp darkens above 233° C. under N2 ; 1H NMR (D2O) ∂ 0.89 (m, 3H), 1.21 to 1.57 (m, 16H), 1.67 (m, 2H), 2.55 (t, J=7.1 Hz, 2H), 7.35 (m, 2H), 7.51 (m, 1H), 7.90 (dd, J=42.4, 26.3 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[N:63]=[C:64]([O:66][CH2:67][CH2:68][O:69][CH3:70])[NH2:65]>CN(C)C=O>[CH3:70][O:69][CH2:68][CH2:67][O:66][C:64]1[N:65]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:63]=1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 300 mg (0.783 mmol) of the carboxylic acid from Example 56A in 10.0 ml of N,N-dimethylformamide were added, at room temperature, 329 mg (0.864 mmol) of HATU and 0.28 ml (205 mg, 1.59 mmol) of N,N′-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 106 mg (0.792 mmol) of 2-methoxyethyl N′-hydroxyimidocarbamate from Example 44A and stirred at room temperature overnight. The reaction solution was subsequently stirred at 120° C. for 2 h. The reaction solution was purified directly by means of preparative HPLC. Yield: 98.0 mg (26% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:38][C:37]([CH:39]=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:38][C:37]([C:39]3[NH:25][C:24]4[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]5[CH:14]=[CH:13][C:12]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][CH2:16]6)=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=Cc1ccc(N2CCOCC2)s1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)s3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 418 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 5-morpholinothiophene-2-carboxaldehyde. [M+H]+ calcd for C26H27N5O3S: 490.18; found: 489.95.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN1C(=O)CCC1.O>[CH:25]1([NH:28][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 100 °C
Yield: 72.5 %

Procedure:
To a mixture of 7-morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]-fluoren-5-one (10.7 g, 32.9 mmol) in NMP (65 mL) was added cyclopropylamine (6.9 mL, 99 mmol). The mixture was heated at 100° C. for 5 h. LC/MS analysis indicated ˜75% conversion to product, therefore a further portion of cyclopropylamine (2.3 mL, 33 mmol) was added, the mixture heated at 100° C. for 4 h and then cooled to ambient. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic portion was washed with sat. aq. NH4Cl (2×50 mL) and brine (50 mL) and then the aqueous portions re-extracted with EtOAc (3×100 mL). The combined organic portions were dried over MgSO4 and reduced in vacuo to give 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea as an orange glassy solid (9.10 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:21][NH:20][CH2:19][CH2:18]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:21][N:20]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:19][CH2:18]2
Reactant: COc1cc2c(c(OC)c1OC)CNCC2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(c(OC)c1OC)CN(CCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 61.8 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (0.34 g), 1,2,3,4-tetrahydro-6,7,8-trimethoxyisoquinoline [0.33 g; J. Chem. Soc. D, (20), 1296-1297 (1970)] and potassium carbonate (0.5 g) in DMF (20 ml) was heated at 50° for 12 h. The mixture was then filtered and the filtrate evaporated. The residue was taken up in water, extracted with dichloromethane, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (0.34 g) as a red solid, MP: 110°. NMR includes signals at d 3.55 (2H,s,N--CH2Ar), 3.70 (6H,s,OCH3), 3.75 (3H,s,OCH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetate (1.25 g, 3.49 mmol) in CH2Cl2 (10 ml) was added TFA (10 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and poured into ice-H2O. The resulting precipitate was collected under a reduced pressure and the crude solid was recrystallized from MeOH—CHCl3—IPE to give 4-[N′-(2-fluorophenyl)ureido]-3-methylphenylacetic acid (830 mg, 79%) as white needles. 1H-NMR (DMSO-d6) δ2.23 (s, 3 H), 3.47 (s, 2 H), 6.96-7.30 (m, 5 H), 7.74-7.76 (m, 1 H), 8.17-8.20 (m, 1 H), 8.33 (s, 1 H), 8.94 (s, 1 H), 12.27 (br s, 1 H); Anal. Calcd. for C16H15FN2O3: C, 63.57; H, 5.00; N, 9.27; F, 6.28. Found: C, 63.28; H, 5.00; N, 9.14; F, 6.43.
Reaction SMILES: C1(C[O:8][C:9](=[O:53])[CH2:10][N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:25]([O:41][C:42](=[O:52])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:24]=2)[CH2:12][C:13](=[O:22])[O:14]CC2C=CC=CC=2)C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C1COCC1>[C:13]([CH2:12][N:11]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:25]([O:41][C:42](=[O:52])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:24]=1)[CH2:10][C:9]([OH:53])=[O:8])([OH:22])=[O:14]
Reactant: [H][H]
Reactant: CCCCCCCCCC(=O)Oc1ccc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)cc1OC(=O)CCCCCCCCC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)Oc1ccc(N(CC(=O)O)CC(=O)O)cc1OC(=O)CCCCCCCCC
Reaction time: 10 h
Yield: 78.5 %

Procedure:
A mixture of 2.2 g of N-[3,4-bis[(1-oxodecyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 20 ml of ethyl acetate and 30 ml of THF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 10 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a semisolid which was crystallized from ethyl acetate-hexane to give 1.3 g (78% yield, mp 131°-133°) of N-(carboxymethyl)-N-[3,4-bis[(1-oxodecyl)oxy]phenyl]glycine.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36](/B(O)O)=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: CCCCCC/C=C/B(O)O
Product: CCCCCCC=Cc1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-1-octen-1-ylboronic acid (47 mg, 0.3 mmol) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(4-oct-1-enyl-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1]CCCCC.C([Li])CCC.[C:12]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CI>O1CCCC1>[CH3:1][CH:13]([CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OCC
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCC(C)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 1.7 g. of n-isopropylcyclohexylamine in 15 ml. of tetrahydrofuran, at -78°, is added 5.5 ml. of a 2.4 N n-butyl lithium n-hexane solution. Then 3 g. of ethyl arachidonate in 150 ml. of tetrahydrofuran is added dropwise, over a 2-hour period, at -78°. Then 1.5 ml. of methyl iodide is added and the mixture is allowed to warm to room temperature. The solution is concentrated by evaporating tetrahydrofuran, then extracted with ether to yield ethyl 2-methylarachidonate.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:36]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:35])=[O:12])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1cccnc1)C(=O)O)OCc1ccccc1
Reactant: CNCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2.5 g of Z-Pal-OH (8.7 mMol) are dissolved in 50 ml of THF, mixed with 1.55 g CDI (9.5 mMol), stirred for 45 minutes at ambient temperature, then mixed with 1.12 ml of N-methyl -benzylamine (8.7 mMol ) and stirred for a further 64 hours at ambient temperature. The reaction mixture is concentrated on the rotary evaporator, the residue is taken up in ethyl acetate, extracted once with cold water and once with 10% NaCl solution. The organic phase is filtered, concentrated and chromatographed over a silica gel column by means of ether as eluant. Z-Pal-N(Me)Bzl is obtained as colourless oil from the eluant. [α]D20 (MeOH )=-0.3°.