Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O.C([O:21][S:22]([O-])(=[O:24])=[O:23])CCCCCCCCCCC.[Na+:26].CCCCC[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O.[Na]>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]1[C:32]([S:22]([O-:24])(=[O:23])=[O:21])=[CH:33][CH:34]=[CH:35][CH:36]=1.[Na+:26]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: CCCCCCC
Reactant: CCCCCCCCCCCCCCCC
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCCCCCCCCCCCc1ccccc1S(=O)(=O)[O-]

Procedure:
Values of α reported for a number of anionic surfactants at air-waterand heptane-water interfaces range from 45 to 72 Å2 . Oh and Shah estimated α of sodium dodecylsulfate at hexadecane/water and air/water interfaces as 68.9 and 5.18 Å2 respectively. Sodium dodecylbenzosulfonate (SDBS), an anionic surfactant, exhibited saturation adsorption on graphon, a hydrophobic surface, at the CMC, with α value of 60 Å2. We obtained α value of 61 Å2 for SDBS at decane-water interface, from a plot of interfacial tension, γ, versus the lnC, using the Wilhelmy plate technique for measuring γ.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1)=O.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C1COCC1.[BH4-].[Na+]>CO>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[NH:5][CH:4]=2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1ccnc2[nH]cc(C=O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccnc2[nH]cc(CNC3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
Methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (160 mg, 0.784 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (188 mg, 0.940 mmol) were combined in MeOH (3 mL) and THF (3 mL) at 50° C. for 3 H. Then sodium borohydride (59 mg, 1.567 mmol) was added at room temperature and allowed to stir for 10 min. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo to give methyl 3-((1-(tert-butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (60 mg) which was carried on to the next step. 1H NMR (400 MHz, CD3OD) δ 8.32 (d, 1H, J=5.1 Hz), 7.61-7.62 (m, 2H), 4.07-4.13 (m, 4H), 4.01 (s, 3H), 2.81-2.84 (m, 3H), 1.96-1.98 (m, 2H), 1.45-1.47 (m, 2H), 1.45 (s, 9H). [M+H] found 389.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH:32]=[N:31][CH:30]=[N:29]1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([CH2:33][N:28]4[CH:32]=[N:31][CH:30]=[N:29]4)=[CH:35][CH:36]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Nc1ccc(Cn2cncn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cn2cncn2)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 100 mg; 0.36 mmol) in DCM (4 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) followed by triethylamine (100 mL; 0.73 mmol) and 4-((1H-1,2,4-triazol-1-yl)methyl)aniline (Maybridge, 63.2 mg; 0.36 mmol). After stirring at RT for 24 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH2:26][CH2:27][CH2:28][C:29]3[N:30]=[CH:31][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:33]=3)[CH:20]=2)[C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[CH2:4][CH2:3]1.C1(O)C=CC=CC=1.Cl[Si](C)(C)C>ClCCCl>[N:32]1[CH:33]=[C:29]([CH2:28][CH2:27][CH2:26][S:25][C:21]2[CH:20]=[C:19]([CH:9]([O:8][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:10]3[NH:11][C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[N:14]=3)[CH:24]=[CH:23][CH:22]=2)[NH:30][CH:31]=1
Reactant: CN1CCC(OC(c2cccc(SCCCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2)c2nc3ccccc3[nH]2)CC1
Agent: C[Si](C)(C)Cl
Solvent: Oc1ccccc1
Solvent: ClCCCl
Product: CN1CCC(OC(c2cccc(SCCCc3cnc[nH]3)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
To a solution of 2-((1-methylpiperidin-4-yloxy){3-[3-(1-trityl-1H-imidazol-4-yl)propylsulfanyl]phenyl}methyl)-1H-benzimidazole (200 mg) in 1,2-dichloroethane (7 mL) are added phenol (270 mg) and chlorotrimethylsilane (0.37 mL). The reaction mixture is heated at reflux overnight. Volatiles are removed under reduced pressure and the residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to give 2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([NH:26][C:27](=[NH:33])[N:28]2[CH:32]=[CH:31][CH:30]=N2)=[O:25])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1.NCCC[OH:38].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([NH:26][C:27]([NH:28][CH2:32][CH2:31][CH2:30][OH:38])=[NH:33])=[O:25])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Reactant: NCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)NCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[imino(1H-pyrazol-1-yl)methyl]acetamide (0.240 g, 0.50 mmol) in CH2Cl2 (5 mL) was added 3-aminopropanol (0.112 g, 0.12 mL, 1.50 mmol) and diisopropyl ethylamine (0.193 g, 0.26 mL, 1.50 mmol). The solution was stirred overnight at RT. The solvent was removed and the product purified by flash chromatography (15:1 CHCl3:MeOH) to yield 2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide as a white solid. mp 49-50° C.; MS (ES) m/z 486.09 ([M+H]+). MS (ES) m/z 971.26 ([2M+H]+). Anal. Calcd for C25H28ClN3O3S.0.10 C6H14: C, 62.16; H, 5.99; N, 8.49. Found: C, 62.41; H, 5.70; N, 8.45.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[CH:5]=[N:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[C:10]([O:9][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OCc1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CC(=O)OCc1cncc(-c2ccc(F)cc2)c1

Procedure:
5-Bromo-3-acetoxymethylpyridine is reacted with 4-fluorobenzeneboronic acid as described in Example 1. The 5-(4-fluorophenyl)pyridin-3-ylmethyl acetate obtained is saponified by conventional methods and subsequently oxidized to give 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: ClCCCCSc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(4-chlorobutyl)sulfanyl]benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 410.6 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:5]=2[NH:4][C:3]1=S.[C:23]([NH:26][NH2:27])(=O)[CH3:24]>C(O)C>[CH3:24][C:23]1[N:4]2[C:5]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])=[N:8][CH:2]([CH3:1])[C:3]2=[N:27][N:26]=1
Reactant: Cc1cc(C)c2c(c1)NC(=S)C(C)N=C2c1ccccc1Cl
Reactant: CC(=O)NN
Solvent: CCO
Product: Cc1cc(C)c2c(c1)-n1c(C)nnc1C(C)N=C2c1ccccc1Cl
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 3,6,8-trimethyl-1,3-dihydro-5-(o-chlorophenyl)- 2H-1,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and the resulting product heated to 250° C. to give 1,4,7,9-tetramethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[C:16]([C:18]([OH:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[N:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.O>CC(C)=O.Cl>[OH:21][C:18]([C:16]1[CH:15]=[C:14]([C:22]([F:24])([F:25])[F:23])[N:13]=[C:12]([O:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:17]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(O)c1cc(OC2CCC(=O)CC2)nc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[2-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-6-(trifluoromethyl)pyridin-4-yl]propan-2-ol (0.049 g, 0.14 mmol) was dissolved in acetone (3.7 mL) A solution of 12.0 M hydrogen chloride in water (0.43 mL, 5.2 mmol) was added and was stirred at 25° C. for 16 hours at which time LCMS showed about 70% reaction was complete. An additional 12.0 M hydrogen chloride in water (0.43 mL, 5.2 mmol) was added and was stirred for 3 hours; LCMS showed ˜90% reaction was complete and was quenched into excess NaHCO3, extracted with EtOAc and the organic extract was evaporated to give the product. This was used in the next reaction without purification. MS (ES): 318 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[F:24][C:25]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[CH:28]=[CH:27][C:26]=1[CH3:34]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:31]([C:29]3[CH:28]=[CH:27][C:26]([CH3:34])=[C:25]([F:24])[CH:30]=3)[C:32]2=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cc1ccc(N=C=O)cc1F
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(C)c(F)c3)c(=O)n(C3CCCC3)c12
Yield: 66.8 %

Procedure:
1-Cyclopentyl-3-(3-fluoro-4-methyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (28 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-fluoro-5-isocyanato-2-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 420 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH:20]1([Mg]Br)[CH2:22][CH2:21]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:20]1[CH2:22][CH2:21]1)([CH:17]1[CH2:18][CH2:19]1)[OH:16]
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Reactant: Br[Mg]C1CC1
Product: Nc1ccc(-c2cccc(Cl)c2)cc1C(O)(C1CC1)C1CC1

Procedure:
(4-Amino-3′-chloro-biphenyl-3-yl)-dicylopropyl-methanol (mp 90-92° C.; MS ((+)ESI) m/z 314 (M+H)+.) was prepared from (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone and cyclopropylmagnesium bromide according to Example 41.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][NH:35][CH3:36])[CH3:31]>C(Cl)Cl>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][N:35]([C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[CH3:36])[CH3:31]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CNC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a stirred solution of (tert-butoxycarbonyl-methyl-amino)-acetic acid (37 g, 0.2 mol) and Et3N (60.6 g, 0.6 mol) in CH2Cl2 (300 mL) was added isobutyl chloroformate (27.3 g, 0.2 mmol) dropwise at −20° C. under argon. After stirring for 0.5 h, methylamino-acetic acid ethyl ester hydrochloride (30.5 g, 129 mmol) was added dropwise at −20° C. The mixture was allowed to warm to room temperature (c.a. 1 h) and quenched with water (500 mL). The organic layer was separated, washed with 10% citric acid solution, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc 1:1) to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid ethyl ester (12.5 g, 22%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[N:19]([CH3:21])[N:20]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:37]([N:39]([CH2:45][CH3:46])[CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)[CH3:38].CCN(CC)CC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[C:18]([C:22]([N:42]2[CH2:43][CH2:44][CH:40]([N:39]([CH2:45][CH3:46])[CH2:37][CH3:38])[CH2:41]2)=[O:23])[N:19]([CH3:21])[N:20]=1
Reactant: Cn1nc(-c2ccccc2-c2cc3ccccc3o2)cc1C(=O)O
Reactant: CCN(CC)C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C1CCN(C(=O)c2cc(-c3ccccc3-c3cc4ccccc4o3)nn2C)C1
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A solution of 0.124 g (0.39 mmol) of 5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid in 1.28 ml of DMF was treated with 0.063 g (0.39 mmol) of CDI. After 4 h, 0.055 g (0.39 mmol) of 3-(diethylamino)pyrrolidine and 0.217 ml (1.56 mmol) of Et3N in 1.28 ml of DMF were added and stirring was continued for 2 h. The solution was partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried (Na2SO4) and evaporated. The crude product was crystallized with Et2O/pentane to give 0.130 g (75%) of [5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone as light pink powder. MS: 443.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[C:28](=[O:36])[C:29](=[O:35])[C:30]=5[NH:31][CH:32]([CH3:34])[CH3:33])[CH:25]=4)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[C:28](=[O:36])[C:29](=[O:35])[C:30]=5[NH:31][CH:32]([CH3:33])[CH3:34])[CH:25]=4)[NH:20][CH:19]=3)[CH2:13][CH2:14]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ccc(-c4c(NC(C)C)c(=O)c4=O)cc23)CC1
Solvent: CC#N
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(-c4c(NC(C)C)c(=O)c4=O)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-isopropylamino-3-cyclobuten-3-yl) -1-triisopropylsilylindole (0.270 g, 0.42 mmol) in 10 mL of acetonitrile was added 48% HF (30 μL, 0.84 mmol) and the mixture was stirred at room temperature for 2 h. The resulting mixture was evaporated and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The organic phase was separated and the aqueous phase was back-extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and evaporated to give a yellow foam. Crystallization from ethanol at -20° C. afforded the title compound (0.192 g, 94%) as a light yellow solid, mp 104°-106° C.: IR (KBr) 3230 (br), 1768, 1710, 1580 (br) cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.15 (s, 1H), 8.77 (d, J=8.6 Hz, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H), 4.59 (m, 1H), 4.35 (t, J=5.1 Hz, 2H), 3.82 (s, 3H), 3.68 (br s, 4H), 3.43 (m, 1.7H, CH3CH2OH), 2.78 (t, J=7.4 Hz, 2H), 2.5-2.3 (m, 6H), 1.86 (m, 2H), 1.31 (d, J=6.5 Hz, 6H), 1.05 (t, J=7.0 Hz, 2.6H, CH3CH2OH). Anal. Calcd for C24H26N6O3. 0.5 H2O. 0.85 C2H6O: C, 64.22; H, 7.15; N, 15.66. Found: C, 64.30; H, 6.78; N, 15.48.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:24][CH:25]([CH3:60])[C:26]([NH:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[NH:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[C:47]([Cl:59])[CH:46]=1)=[O:27]>C1COCC1>[Cl:59][C:47]1[CH:46]=[C:45]([NH:44][C:32]2[C:31]3[C:36](=[CH:37][C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[C:29]([NH:28][C:26]([C@H:25]([NH:24][C:1](=[O:5])[CH:2]=[CH2:3])[CH3:60])=[O:27])[CH:30]=3)[N:35]=[CH:34][N:33]=2)[CH:50]=[CH:49][C:48]=1[O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: C=CC(=O)O
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)C(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)N[C@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
75 μl of acrylic acid was dissolved in 4 ml of THF, and cooled to 0° C. 180 μl of pyridine and 520 ml of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added thereto, the resulting solution was reacted with 284 mg of 2-amino-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(2-methoxy-ethoxy)-quinazolin-6-yl]-propionamide dissolved in 4 ml of THF as a starting material for 30 mins, and then stirred for 3 hours while heating to room temperature. The reacted solution was washed with saturated sodium bicarbonate solution, extracted with a mixture of chloroform and methanol, dried over sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (87 mg, 28%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][CH2:30][C@H:31]([OH:44])[C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=4)=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CO>[OH:44][C@H:31]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=1)[CH2:30][NH:29][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][CH:17]2[CH2:16][CH2:15][N:14]([C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)=[O:13])[CH2:19][CH2:18]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)cc3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCc2ccc(NC3CCN(C(=O)N4CCC(C(=O)O)CC4)CC3)cc2)ccc1O
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a solution of 1-[4-(4-(2-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-ethyl)-phenylamino)-piperidine-1-carbonyl]-piperidine-4-carboxylic acid ethyl ester (0.135 g, 0.213 mmol) was dissolved in methanol (5 mL) and sodium hydroxide (0.5 mL, 1N, 0.5 mmol) was added. The mixture was stirred at ambient temperature for thirty minutes and 1N hydrochloric acid (0.55 mL, 0.55 mmol) was added. The solvent was removed and the mixture partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate and the solvent removed in vacuo to yield the title compound (0.031 g, 0.05 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13]C(=O)C2C=CC=CC=2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>[Ni]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(OC(=O)c2ccccc2)cc1OC
Agent: [Ni]
Product: COC(=O)c1ccc(O)cc1OC

Procedure:
The product obtained in Stage B is hydrogenated in an autoclave in the presence of alcohol with Raney nickel as catalyst. The hydrogenation is done at 50° C and lasts 21/2 hours. It is cooled, the nickel drained and the alcohol removed under vacuum. The methyl 2-methoxy-4-hydroxybenzoate formed crystallizes and is used for the following stage.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)CCC/C=C\CC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Agent: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)O
Product: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O

Procedure:
This compound was prepared as described above for (6) using 0.5 mmol (151 mg) of cis-5,8,11,14,17-eicosapentaenoic acid; yield 84 mg, (36%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.5-1.6 (t, 2H, CH2); 2.0-2.2 (m, 6H, CH2CO and 2 CH2CH═CH); 2.7-2.9 (br s, 8H, 4HC═CH—CH2—CH═CH); 3.9-4.0 (br s, 2H, CH2OP); 4.3-4.4 (m, 1H, NH CHCO); 5.2-5.4 (br s, 10H, 5 HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [N:1]1[O:2][C:3]([C:10]([OH:12])=O)=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH2:32])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH:32][C:10]([C:3]5[O:2][N:1]=[C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=56)=[O:12])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1onc2ccccc12
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1onc2ccccc12
Yield: 32.2 %

Procedure:
A mixture of benzo[c]isoxazole-3-carboxylic acid (46 mg, 0.28 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.33 mmol), EDC (64 mg, 0.33 mmol) and HOBt (45 mg, 0.33 mmol) was stirred at room temperature in DMF (2.5 ml) for 20 h. The mixture was reduced in vacuo and the residue partitioned between EtOAc (5 ml) and water (2 ml), the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-MeOH (100:0-90:10)] to give benzo[c]isoxazole-3-carboxylic acid[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide as a white solid (40 mg, 32%). (LC/MS: Rt 2.13, [M+H]+ 444).