Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49]([C:52](OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:59][CH3:60])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]([CH2:51][CH3:50])[CH2:47][CH2:48][NH:49][CH3:52])[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN(CC)CCNC)c3)c2)c1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate (0.130 g, 0.16 mmol) in DCM (200 μL) was added TFA (100 μL, 0.1298 mmol) after which the mixture was stirred at room temperature for ¼ h. The reaction mixture was concentrated under vacuum, purified using a Gilson HPLC (with 0.1% TFA), and product concentrated using a GeneVac EZ-2 evaporator at 45° C. for 8 h. Extra TFA was removed by re-dissolving the resultant mixture in DCM and passing it though an amino cartridge to afford 0.0555 g (48%) of the title compound. LC-MS m/z 716 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.39 (t, J=7.53 Hz, 3H) 1.48 (t, J=7.28 Hz, 3H) 1.80-1.95 (m, 2H) 2.08 (d, J=12.30 Hz, 2H) 3.15 (q, J=7.53 Hz, 2H) 3.57 (s, 8H) 3.62-3.72 (m, 2H) 4.02 (dd, J=8.41, 3.14 Hz, 2H) 4.27-4.39 (m, 1H) 4.43-4.52 (m, 4H) 4.64 (s, 2H) 4.70 (s, 2H) 7.35-7.46 (m, 2H) 7.46-7.63 (m, 4H) 7.65 (s, 1H) 7.73 (d, J=7.53 Hz, 1H) 7.81 (s, 1H) 8.05 (d, J=7.78 Hz, 2H) 8.27 (s, 1H) 8.40 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([N:6]1[CH:10]=[N:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[N:7]1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]([N:6]1[CH:10]=[N:9][C:8]([S:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:13]=2[Cl:22])=[O:33])=[N:7]1)=[O:5])[CH3:24]
Reactant: CCN(CC)C(=O)n1cnc(Sc2ccc(C(F)(F)F)cc2Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)n1cnc(S(=O)c2ccc(C(F)(F)F)cc2Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
1-(Diethylcarbamoyl)-3-(2-chloro-4-trifluoromethylphenylthio)-1,2,4-triazole (3.79 g) is dissolved in chloroform (100 ml). With the temperature held at 10° C. or below with ice water, m-chloro-perbenzoic acid (1.73 g) is added in small portions over a period of 10 minutes. Thereafter, reaction is performed at 10° C. for 2 h, then at room temperature for 10 h. The chloroform solution is washed twice with a 10% aqueous solution of potassium carbonate (100 ml), then washed with water, and dried with magnesium sulfate. When the solvent is distilled off, an oil remains. This is purified by silica gel chromatography (solvent 1:1 mixture of chloroform and n-hexane) to produce the titled compound, 1-(diethylcarbamoyl)-3-(2-chloro-4-trifluoromethylphenylsulfinyl)-1,2,4-triazole (2.7 g) as an oil; yield, 68.4%.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>S(=O)(=O)(O)O.O>[C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])[NH2:2]
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCNC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@H]1CCNC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-(R)-(-)-(1-cyano-1,1-diphenylmethyl)pyrrolidine (9.2 g-see Preparation 9(B)) was dissolved in 95% sulphuric acid (80 ml) and the mixture was heated at 80° C. for 4 hours and then at 90° C. for 1 hour. Ice (1 kg) was added and the mixture was basified (pH 12) by the addition of a cold solution of sodium hydroxide (120 g) in water (100 ml). The mixture was extracted with dichloromethane (4×100 ml) and the combined extracts were dried (MgSO4) then concentrated in vacuo to give a foam which was purified by column chromatography on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield, 4.5 g, [α]D25 +16.9° (c 1.0, CH2Cl2).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:13](=[C:14]([NH:16][C:17]([C@@H:19]3[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[CH2:21][N:20]3[CH2:27][C@@H:28]([NH2:30])[CH3:29])=[O:18])[CH:15]=1)[NH:12][C:11]1[CH:10]=[N:9][CH:8]=[CH:7][C:6]2=1.C(Cl)Cl.Cl[C:35]([O:37][CH3:38])=[O:36].O>N1C=CC=CC=1>[CH3:38][O:37][C:35](=[O:36])[NH:30][C@@H:28]([CH3:29])[CH2:27][N:20]1[C@H:19]([C:17](=[O:18])[NH:16][C:14]2[CH:15]=[C:3]([Cl:2])[CH:4]=[C:5]3[C:13]=2[NH:12][C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]3=2)[CH2:24][O:23][C:22]([CH3:25])([CH3:26])[CH2:21]1
Reactant: COC(=O)Cl
Reactant: C[C@H](N)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of (S)-4-((S)-2-Amino-propyl)-6,6-dimethyl-morpholine-3 carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide hydrochloride salt (3.45 g, 6.59 mmole) in 68 ml of dry pyridine, was added in three portions over 1.5 hr, a 3M DCM solution of methyl chloroformate (9.2 ml, 27.6 mmole, 4.2 eq). After 2 h, 10 ml of water were added and the mixture was concentrated to dryness. The residue was partitioned into 150 ml Of EtOAc and 100 ml of an aqueous 0.5M solution of K2CO3. The separated aqueous phase was extracted with 50 ml of EtOAc. The combined organic extracts were successively washed with water (2×50 ml) and brine (50 ml), dried over Na2SO4 and concentrated to dryness. The residue was purified on silica (5% MeOH/CH2Cl2) to give 2.48 g(thick oil, 77% yield) of the desired product.
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[C@H:9]([OH:16])[CH2:8][C@H:7]1[C@@H:6]1[CH2:17][CH2:18][C:19]3[C@@:25]([CH3:26])([C@@:5]1([F:27])[C@@H:4]([OH:28])[CH2:3]2)[CH:24]=[CH:23][C:21](=[O:22])[CH:20]=3.C([C:32]([NH2:34])=O)(=O)C.Cl(O)(=O)(=O)=O>ClCCl>[CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[C@H:9]([OH:16])[CH2:8][C@H:7]1[C@@H:6]1[CH2:17][CH2:18][C:19]3[C@@:25]([CH3:26])([C@@:5]1([F:27])[C@@H:4]([OH:28])[CH2:3]2)[CH:24]=[CH:23][C:21](=[O:22])[CH:20]=3.[C:4]([CH2:3][CH2:2][CH2:10][C:9]([NH:34][CH3:32])=[O:16])(=[O:28])[CH3:5]
Reactant: CC(=O)C(N)=O
Agent: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CNC(=O)CCCC(C)=O

Procedure:
(VI) or triamcinolone is reacted with an acetylcarboxamide in a solution of dichloromethane in the presence of catalytic amount of perchloric acid to produce the corresponding 16α,17-aminocarbonylcyclic acetal pregnane derivatives, e.g., when triamcinolone and acetylpropyl (N-methyl) carboxamide are used the product is (XVIII) 9α-fluoro-11β, 21-dihydroxy-3,20-dioxo-16α,17-(methyl,methylaminocarbonyl-n-propyl)methylenedioxy-1,4-pregnadiene;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([N+:16]([O-])=O)=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[C:23]([CH3:36])=[CH:22][N:21]=1.[NH4+].[Cl-].C(Cl)Cl.CO>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([NH2:16])=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[C:23]([CH3:36])=[CH:22][N:21]=1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
A mixture of N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 78, 408 mg, 0.84 mmol), iron (280 mg, 5.02 mmol) and NH4Cl (31.3 mg, 0.59 mmol) in ethanol (24 mL) and water (8.00 mL) was heated at reflux for 3 h. The mixture was cooled and concentrated in vacuo to give a thick slurry. CH2Cl2 (100 mL) and CH3OH (10 mL) were added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with further CH2Cl2 and CH3OH and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-7% methanolic ammonia in CH2Cl2 gave the title compound (163 mg, 43%) as a yellow gum which crystallised on standing; 1H NMR: (CDCl3) 2.36 (6H, s), 2.53 (3H, dd), 2.94 (4H, t), 3.69-3.79 (2H, m), 3.83 (3H, s), 3.86 (3H, s), 6.69 (1H, s), 7.24-7.27 (1H, m), 7.29 (1H, dd), 7.33 (1H, dd), 7.36-7.40 (1H, m), 7.49 (1H, s), 7.58 (1H, s), 8.23 (1H, d), 8.26 (1H, s), 8.56 (1H, d); m/z: ES+ MH+ 458.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A mixture of 4-chloro-2-fluoro-1-nitrobenzene (983 mg, 5.60 mmol) and aniline (1.0 mL, 11.20 mmol) in DMSO (3 mL) was heated at 110° C. for 4 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with a saturated aqueous solution of KHSO4 (×3), followed by brine, then dried (Na2SO4) and concentrated in vacuo to afford the title compound as an orange solid (1.37 g, 98%). 1H NMR (CDCl3, 400 MHz): δ 9.54 (1H, s), 8.16 (1H, d, J=9.13 Hz), 7.46 (2H, t, J=7.61 Hz), 7.32-7.22 (3H, m), 7.14 (1H, d, J=2.14 Hz), 6.72 (1H, dd, J=9.12, 2.15 Hz)
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]([CH2:50][CH3:51])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:43])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])([OH:3])=[O:2].I[CH:53](C)C>>[C:1]([CH2:4][CH2:5][N:6]([CH:50]([CH3:53])[CH3:51])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:43])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])([OH:3])=[O:2]
Reactant: CC(C)I
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CCC(=O)O)C(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2-carboxyethyl)(ethyl)amino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (example 89) using 2-iodopropane as alkylating reagent. The product was isolated as a white solid (12 mg, 66%). LCMS: m/e 715.62 (M+H)+, 2.08 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=7.93 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.88 Hz, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 4.00-3.85 (m, 1H), 3.85-3.65 (m, 2H), 3.55-3.32 (m, 4H), 3.23-3.08 (m, 1H), 3.01-2.87 (m, 2H), 2.64-2.47 (m, 1H), 2.27-2.14 (m, 2H), 1.75 (s, 3H), 1.41 (d, J=4.88 Hz, 6H), 2.04-1.10 (m, 19H), 1.08 (s, 3H), 1.06 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cn1c2c(c(=O)n1-c1cccc(Br)c1)[C@H]1CC[C@]2(C)C1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: Cn1c2c(c(=O)n1-c1cccc(-c3ccccc3)c1)[C@H]1CC[C@]2(C)C1(C)C
Yield: 18.1 %

Procedure:
A degassed mixture of 2-(3-bromo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 22; 75 mg, 0.2 mmol), phenyl-boronic acid (38 mg, 0.3 mmol), potassium phosphate (132 mg, 0.62 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 0.024 mmol) in dimethoxyethane (3 mL) was sealed under argon and heated at 80 degrees overnight and then at 60 degrees over the weekend. The reaction mixture was filtered and the residue was washed with dimethoxyethane. The solvent was evaporated from the filtrate and the residue was purified by chromatography on a Sep-Pak column, eluting with 15% ethyl acetate/hexanes to give (4S,7R)-2-biphenyl-3-yl-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (13 mg, 17%) as a white solid. ES(+)-MS (M+H) 359.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:13]1[CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]1>CO>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][CH2:14][CH:15]([OH:13])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCCCC1CO1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Solvent: CO
Product: CCCCC(O)CNCc1ccc(S(C)(=O)=O)cc1
Yield: 37.6 %

Procedure:
A solution (50 ml) of 4-methanesulfonylbenzylamine (5.0 g) and 1,2-epoxyhexane (3.25 g) in methanol was stirred at room temperature for 96 hrs. The reaction-mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=10:1) to give the title compound (2.9 g).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([O:10]C(=O)C)[CH:7]=[CH:8][CH:9]=1.C[O:15][C:16]([C:18]1([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([OH:37])[CH:30]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17]>>[OH:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][O:37][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=2[O:35][CH3:36])[C:28]([NH:27][C:18]2([C:16]([OH:15])=[O:17])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26]2)=[O:38])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Reactant: CC(=O)Oc1cccc(CCO)c1
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(O)c1

Procedure:
The compound of step 1 and the compound of step 2 of example 15 were reacted in analogy to step 3 of example 15 and the obtained ester hydrolyzed in analogy to example 16.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-]>CCO>[CH2:12]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Yield: 75.5 %

Procedure:
Ethyl isonipecotate (212 g, 1.35 mole), benzyl chloride (170 g, 1.35 mole), and potassrum carbonate (322 g, 233 mole) were stirred at room temperature in absolute EtOH (1.8 L) for 72 hours. The crude mixture was filtered through Celite, rinsed with Et2O, and concentrated in vacuo. The resulting mixture was diluted with Et2O, and extracted with H2O (3x), then brine, dried (MgSO4), and concentrated in vacuo. The product was distilled under high vacuum, bp 128°-130° C. at 0.8 mm Hg, to yield 252 g of a colorless liquid (76%). Analysis: Calculated for C15H21NO2 : C,72.84; H,8.56; N,5.66; found: C,72.91; H,8.38; N,5.88
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:37])[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[C:22]4([NH:25][C:26](=[O:32])[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:23][CH2:24][CH:19]([CH2:20][CH2:21]4)[CH2:18][N:17]3[C:33](=[O:36])[C:34]=2[OH:35])=[O:13])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O>CN(C=O)C>[CH2:45]([O:35][C:34]1[C:33](=[O:36])[N:17]2[CH2:18][CH:19]3[CH2:24][CH2:23][C:22]([NH:25][C:26](=[O:32])[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])([C:16]2=[N:15][C:14]=1[C:12](=[O:13])[NH:11][CH2:10][C:9](=[O:37])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:21][CH2:20]3)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCC(=O)Cc2ccc(F)cc2)c(O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCC(=O)Cc2ccc(F)cc2)c(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To a mixture of N′-(2-((3-(4-fluorophenyl)-2-oxopropyl)carbamoyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)-N,N-dimethylethanediamide, Intermediate 15 (140 mg, 0.273 mmol) in DMF (5 mL) was added K2CO3 (67.8 mg, 0.491 mmol) followed by (bromomethyl)benzene (0.049 mL, 0.409 mmol) and the resulting mixture stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography to afford the title compound (140 mg, 0.162 mmol, 59.5% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 8.73 (1H, s), 8.31 (1H, s), 7.53-7.59 (2H, m), 7.31-7.38 (3H, m), 7.18-7.24 (2H, m), 7.02-7.07 (2H, m), 5.35 (2H, s), 4.73 (2H, s), 4.29 (2H, d, J=5.49 Hz), 4.16 (2H, d, J=3.66 Hz), 2.94 (3H, s), 2.91 (3H, s), 2.70-2.79 (2H, m), 2.53 (1H, br. s.), 1.98-2.12 (4H, m), 1.70-1.80 (2H, m). LCMS (M+H)=604.31.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:27])[CH2:15][NH2:16])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)N1CCN(C(=O)CN)CC1
Reaction time: 12 h

Procedure:
To a solution of 6.34 g 4-(2-Benzyloxycarbonylamino-acetyl)-piperazine-1-carboxylic acid butyl ester in 120 ml ethanol were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethanol and concentrated.
Reaction SMILES: CC(C(N=NC1C(C(O)=O)=CC=CC=1)C(N[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:15]([NH:17][C:10]=2[CH:9]=1)=[O:16])=O)=O.[OH-].[Na+]>O>[N:14]1[C:15](=[O:16])[N:17]=[C:10]2[CH:9]=[CH:8][CH:13]=[CH:12][C:11]=12
Reactant: CC(=O)C(N=Nc1ccccc1C(=O)O)C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1N=c2ccccc2=N1
Reaction time: 5 h

Procedure:
130 g of the aqueous dispersion of the pigment derivative (a) and 30 g of deionized water were mixed with 20 g of C.I. pigment yellow 151 having an average primary particle diameter of 80 nm (in which the content of metal ions having a valence of at least 2 was 270 ppm), a 1% sodium hydroxide aqueous solution was added so as to adjust the pH of a mixture liquid to 9.0, and the mixture liquid was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 5 hours, to obtain a water-based pigment dispersion. In the water-based pigment dispersion, the neutralizatior rate of the sulfonic acid group of the pigment derivative (a) was 80%. Further, the obtained water-based pigment dispersion was diluted so as to have a concentration of 3% by weight, and the diluted water-based pigment dispersion was dropped to NO.2 filter paper, to show no bleedings.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:33][CH2:32]1.O>C1COCC1>[CH2:40]([O:39][C:37]([N:34]1[CH2:35][CH2:36][C:31](=[CH:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[CH2:32][CH2:33]1)=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(=CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
To a suspension of phosphonium bromide 78NLS66 (4.69 g, 10.1 mmol) in THF (100 mL) n-butyllithium (1.6 M in hexane, 6.3 mL, 10.1 mmol) was added at 0° C., giving a deep red solution. After stirring for 1 h at rt, a solution of benzyl 4-oxo-1-piperidinecarboxylate (2.24 g, 9.6 mmol) in THF (10 mL) was added dropwise over 30 min. The mixture was stirred at rt for 20 h, then water was added and the mixture extracted three times with diethylether. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 0-10% ethyl acetate in n-heptane, afforded the title compound (0.56 g, 17%) as a colourless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl-:15].[Ca+2].[Cl-]>C(#N)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: [Cl-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Ca+2]
Solvent: CC#N
Product: O=C(O)CCCCCCCCCCCl
Yield: 102.1 %

Procedure:
To 11-bromoundecanoic acid (1 g) dissolved in acetonitrile (50 ml) were added calcium chloride (2 g) and tetra-n-butylammonium chloride (1.2 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and then distributed into ethyl acetate-water, and the ethyl acetate layer was dried over anhydrous sodium sulfate to give 11-chloroundecanoic acid (0.85 g). After a 230 mg portion of 11-bromoundecanoic acid thus obtained, para-nitrophenol (145 mg) and N,N'-dicyclohexylcarbodiimide (215 mg) in N,N-dimethylformamide (DMF) was stirred for 12 hours, precipitates were removed by filtration and DMF was removed by distillation to give an active ester. To the active ester of 11-chloroundecanoic acid dissolved in DMF (20 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (400 mg) and triethylamine (1.2 ml), and the mixture was stirred for 12 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK133 in the yield of 103 mg.