Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([OH:26])[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([O:26][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1cccnc1
Reactant: O=c1c(Cc2ccccc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cl
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(OCc4cccnc4)cc13)Sc1ccc(Br)cc1-2
Yield: 61.6 %

Procedure:
According to Example 34, the compound (200 mg) produced in Example 70 was reacted with 3-chloromethylpyridine hydrochloride (145 mg) to obtain the title compound (149 mg; 62%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([S:11]([CH3:14])(=[O:13])=[O:12])[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[BH4-].[Na+]>CO>[CH3:14][S:11]([C:2]([CH3:15])([CH3:1])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4])(=[O:13])=[O:12]
Reactant: CC(C)(C(=O)c1cccnc1)S(C)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(O)c1cccnc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.2 %

Procedure:
3-[Dimethyl(methanesulfonyl)acetyl]pyridine (81.0 mg, 0.356 mmol) was dissolved in methanol (2.0 mL). To this, sodium borohydride (20.2 mg, 0.535 mmol) was added under a nitrogen atmosphere at 0° C. and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, water was added thereto, and extraction with ethyl acetate was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol 9/1) to give 3-(2-methanesulfonyl-2-methyl-1-hydroxypropyl)pyridine (Compound CY) (86.7 mg, yield: quantitative).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(Cl)=[O:5])[CH3:2].[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C.O>C(Cl)Cl>[F:17][C:14]([F:15])([F:16])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][P:4](=[O:5])([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[O:3][CH2:1][CH3:2]
Reactant: CCOP(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: OCCN1CCOCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCCN1CCOCC1
Reaction time: 5 h

Procedure:
3-Trifluoromethylbenzylphosphonochloridic acid ethyl ester (7.0 mmol)in 20 mL of CH2Cl2 is added slowly to a mixture of N-(2-hydroxyethyl)morpholine and triethylamine (7 mmol) in 20 mL of CH2Cl2 cooled in an ice bath. The resultant mixture is allowed to reach room temperature and is stirred for 5 hours. Water is added (100 mL) and the aqueous phase is extracted 3 times with CH2Cl2 (3×100 mL). The combined organic extracts are dried with anhydrous MgSO4, and evaporated to give the desired product.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21]=1>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[S:22](=[O:29])(=[O:30])[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: ClC(Cl)Cl
Product: O=S1(=O)N=C(NCCCOc2cccc(CN3CCCCC3)c2)c2ccccc21
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a gently refluxing solution of 3-[3-[(1-piperidinyl)-methyl]phenoxy]propylamine (992 mg, 4 mmol) in 90 ml of chloroform is added dropwise a solution of 880 mg (4.4 mmol) of 3-chlorobenzisothiazole 1, 1-dioxide in 30 ml of chloroform. Following the addition, the reaction mixture is refluxed for an additional 15 min., cooled to room temperature and solvent removed in vacuo. Column chromatography of the resultant residue (foam) on silica gel utilizing methylene chloride:methanol:ammonium hydroxide (90:10:1) as eluting solvent affords after evaporation a white solid. The crude product is suspended in ethyl acetate, filtered and dried to give 620 mg (37.5%) of the title compound, m.p., 138°-140° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][OH:54])=[CH:48][C:25]=1[CH2:26][N:27]1[CH2:47][CH2:46][C:30]2([O:35][CH2:34][CH2:33][N:32]([C:36]([C:38]3[N:39]=[C:40]([CH:43]([CH3:45])[CH3:44])[S:41][CH:42]=3)=[O:37])[CH2:31]2)[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:23][C:24]1[CH:51]=[CH:50][C:49]([CH2:52][CH:53]=[O:54])=[CH:48][C:25]=1[CH2:26][N:27]1[CH2:28][CH2:29][C:30]2([O:35][CH2:34][CH2:33][N:32]([C:36]([C:38]3[N:39]=[C:40]([CH:43]([CH3:44])[CH3:45])[S:41][CH:42]=3)=[O:37])[CH2:31]2)[CH2:46][CH2:47]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4F)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CC=O)ccc4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (0.284 g) was added to a stirred solution of (9-(2-fluoro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 40, step b) (0.21 g) and trifluoroacetic acid (0.046 mL) in DCM (5 mL). After 1 h, ethyl acetate (30 mL) was added followed by a mixture of saturated sodium thiosulphate solution (5 mL) and saturated sodium bicarbonate solution (5 mL). The reaction mixture was shaken well and separated. The ethyl acetate solution was washed with saturated sodium bicarbonate solution, water and brine. Acetic acid (0.07 mL) was added, the solution dried over sodium sulphate, filtered and evaporated in vacuo (bath temperature ˜30° C.) to give the subtitled compound as a gum. Yield 0.2 g. Used directly.
Reaction SMILES: [Cl:1]C1C(C)=C(C=CC=1)N.C1(NC(=O)C)C2CCCCC=2C=CC=1.[Br:24][C:25]1[C:34]2CCC[CH2:30][C:29]=2[C:28]([NH:35][C:36](=[O:38])[CH3:37])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([NH:35][C:36](=[O:38])[CH3:37])=[C:29]([CH3:30])[C:34]=1[Cl:1]
Reactant: Cc1c(N)cccc1Cl
Reactant: CC(=O)Nc1ccc(Br)c2c1CCCC2
Agent: CC(=O)Nc1cccc2c1CCCC2
Product: CC(=O)Nc1ccc(Br)c(Cl)c1C
Yield: 96 %

Procedure:
The title compound was prepared (2.75 g, 96% yield) from commercially available 3-chloro-2-methylaniline by procedures analogous to those described in Experiment 2A and 2B.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:20]=4[C:27]([F:30])([F:29])[F:28])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:31][N:32](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:21]1[C:20]([C:27]([F:30])([F:29])[F:28])=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:31]#[N:32])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 49 %

Procedure:
A mixture of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl) methanone (0.115 g, 0.235 mmol), zinc cyanide (0.055 g, 0.470 mmol), tetrakis(triphenylphosphine)palladium (0.027 g, 0.0235 mmol), and DMF (4 mL) was heated under microwave irradiation at 130° C. for 30 min. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL). The extract was washed with brine (2×80 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-50% EtOAc in hexanes) to give 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (0.050 g, 49%): 1H NMR (300 MHz, CDCl3) δ9.71 (m, 1H), 7.98 (dd, J=9.5, 1.0 Hz, 1H), 7.51 (dd, J=9.5, 1.6 Hz, 1H), 6.95 (d, J=9.5 Hz, 1H), 6.84-6.77 (m, 1H), 5.76 (m, 1H), 5.01-4.96 (m, 1H), 3.46-3.31 (m, 2H), 3.03-2.94 (m, 1H), 2.07-1.70 (m, 4H); MS (ESI+) m/z 436 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[NH2:16].[NH2:17][C:18](N)=[O:19]>O>[CH3:15][O:14][C:10]1[CH:9]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13])[NH:16][C:18](=[O:19])[NH:17][C:6]2=[O:8]
Reactant: NC(N)=O
Reactant: COc1cc(C(=O)O)c(N)c(OC)c1OC
Solvent: O
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2c(OC)c1OC
Temperature: 145 °C
Yield: 45.1 %

Procedure:
A mixture of 4.94 g (21.7 mmols) of 3,4,5-trimethoxyanthranilic acid and 15.15 g (249.8 mmols) of urea was heated at 145° C for an hour with stirring. After cooling, water was added and the mixture was heated at the boiling point with stirring. The solid was taken out by filtration and dried to afford 2.47 g (yield: 45%) of 6,7,8-trimethoxyquinazoline-2,4-dione.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CO>[CH:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:5]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1cccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cccc(COc2cccc(OC)c2C=O)c1
Reaction time: 18 h

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (4.56 g, 0.03 M), methyl 3-bromomethylbenzoate (6.87 g, 0.03 M), anhydrous potassium carbonate (4.455 g), sodium iodide (0.18 g) and methanol (50 ml) were refluxed with stirring for 18 hr. The cooled reaction mixture was filtered and the solid washed well with methanol. The filtrate was evaporated to dryness and the residue triturated with 1 N sodium hydroxide solution. The solid was filtered off and washed with water to give methyl 3-(2-formyl-3-methoxyphenoxy)methylbenzoate, 3.27 g, 36%, m.p. 96°-97° C. from ethyl acetate/petrol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:18]([C:20]1[N:21](S(C2C=CC=CC=2)(=O)=O)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19].[OH-].[Na+].O.P([O-])(O)(O)=O.[Na+]>C(O)(C)C>[NH2:1][C:2]1[N:6]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:18]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19]
Reactant: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccccc5n4S(=O)(=O)c4ccccc4)c3N)c(F)cc2[nH]1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccccc5[nH]4)c3N)c(F)cc2[nH]1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
[5-Amino-1-(6-fluoro-2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl)methanone (114 mg, 0.22 mmol) was dissolved in isopropanol (2.2 ml), and an aqueous solution of 1 M sodium hydroxide (2.2 ml) was added thereto. The resulting mixture was heated at 90° C. with stirring under a nitrogen atmosphere for two hours. After the reaction mixture was cooled to room temperature, water and a saturated aqueous solution of sodium dihydrogen phosphate were added thereto. The product was extracted with ethyl acetate. The organic layer was isolated, washed with an saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (amino silica gel; dichloromethane/methanol=100/5) to give [5-amino-1-(6-fluoro-2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)methanone as a yellow solid (75 mg, 89.8%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH:24]=[CH:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[BH3-]C#N.[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][CH2:24][CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CCN2
Reaction time: 1 h
Yield: 70.2 %

Procedure:
3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-1-(1H-indol-5-ylmethyl)-1H-pyridin-2-one (, from Step 2) (1-7 g, 4.1 mmol) was stirred in 26 mL of acetic acid and NaCNBH3 (0.27 g, 4.3 mmol) was added portionwise. The reaction was stirred for 1 hour. The reaction was diluted water, and washed 5 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 100% EtOAc) gave a white solid (1.2 g, 71%): 1H NMR (300 MHz, DMSO-d6) δ 7.64 (app q, J=8.5 Hz, 1H), 7.34 (dt, J=9.5, 2.6 Hz, 1H), 7.17 (app t, J=8.5, 1H), 6.82 (s, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 6.42 (d, J=8.0 Hz, 1H), 5.48 (br s, 1H), 5.27 (s, 2H), 5.13 (s, 2H), 3.37 (t, J=8.3 Hz, 2H), 2.82 (t, J=8.3 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:5]=21.[C:30](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([NH:29][CH3:30])=[CH:26][CH:27]=[CH:28][C:5]=21
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(N)cccc32)cc(Br)c1OC
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: O
Product: CNc1cccc2c3c(ccc12)C(c1cc(Br)c(OC)c(OC)c1)C(C#N)=C(N)O3
Reaction time: 1 h
Yield: 90.1 %

Procedure:
2,7-Diamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (10) (45 mg, 0.1 mmol) and potassium carbonate (14 mg, 0.1 mmol) were taken in dry acetonitril (5 ml) at room temperature, stirred for 1 h, charged with iodomethane (15.6 mg, 0.11 mmol) and stirred further at room temperature under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (42 mg, 89.9%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[CH2:20]([NH2:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:20]([NH:29][C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)nc(Cl)nc32)C[C@@H]1O
Product: CCCCCCCCCNc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1

Procedure:
The compound 115 is prepared from compound 102 (9.5 g, 22 mmol) and nonylamine (9.58 g, 67 mmole) as per example 103. The crude product was evaporated to dryness and the residue was co-evaporated with a mixture of ethanol and toluene (three times). The resulting residue was dissolved in ethanol and cooled to yield a small amount of product. It was filtered and the filtrate evaporated to dryness. The residue was used without characterization.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:4].[I-:20].[Na+]>CC(C)=O.O>[I:20][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:4]
Reactant: [I-]
Reactant: COc1ccccc1OCC1SCCN1C(=O)CCl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccccc1OCC1SCCN1C(=O)CI
Yield: 75.7 %

Procedure:
A solution of 3-α-chloroacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine (6 g) in acetone (80 ml) is heated to reflux temperature in the presence of sodium iodide (5 g) for 3 hours and then poured in ice and water (400 ml). The precipitate is collected, dissolved in methylene dichloride and washed with water, 5% aqueous NaHCO3, 2N sodium thiosulphate, water and dried on Na2SO4. After the usual workup, the residue is crystallized from acetone and isopropanol to give 5.92 g of 3-α-iodoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine m.p. 81°-83° C. Using in this procedure sodium bromide, the 3-α-bromoacetyl-2-(o-methoxyphenoxy)methyl-thiazolidine is obtained, m.p. 82°-84° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8])[N:5]=[C:4]([CH2:15][CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH2:29][C:30](OC)=O)=[CH:23][C:22]=2[O:21]1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH2:29][C:30]3[NH:19][C:17](=[O:18])[C:3]4[C:4]([CH2:15][CH3:16])=[N:5][N:6]([CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8])[C:2]=4[N:1]=3)=[CH:23][C:22]=2[O:21]1
Reactant: CCCCCCC(C)n1nc(CC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(C)n1nc(CC)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 26.3 %

Procedure:
10 mg (0.037 mmol) of 5-amino-3-ethyl-1-(2-octyl)-1H-pyrazole-4-carboxamide and 30 mg (0.129 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4 mg (25%) of a solid, Rf=0.76 (dichloromethane/methanol=15:1).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[CH:10]([CH3:21])[CH2:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.[OH-].[Na+].Cl>O1CCCC1>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([CH2:11][CH:10]([CH3:21])[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:23])=[O:2])=[O:22])=[O:20]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)C(C)CC(=O)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CC(=O)c1cccc(F)c1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.98 g. portion of 1-[3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline methyl ester (Example 44) is dissolved in 2 ml. of tetrahydrofuran and 20 ml. of 1 N sodium hydroxide is added. The mixture is stirred at room temperature for 4 hours, cooled in an ice bath, acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic extract is washed with sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to a gum. This gum is triturated with ether giving the desired product as 500 mg. of a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[C:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:11][C:12]([O:14][CH3:15])=[O:13].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:38][S:39]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16](=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:41])=[O:40]
Reactant: COC(=O)CC(CCCCCCCCO)=C(CCCCCCCCO)CC(=O)OC
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(CCCCCCCCOS(C)(=O)=O)=C(CCCCCCCCOS(C)(=O)=O)CC(=O)OC
Temperature: 0 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
To a flamed-dried 20 mL vial fitted with a screw-cap septa was added Dimethyl 3,4-bis(8-hydroxyoctyl)hex-3-enedioate (1 equiv, 0.642 mmol, 275 mg), CH2Cl2 (6 mL), and Et3N (4 equiv, 2.57 mmol, 0.36 mL). The mixture was cooled to 0° C. and DMAP (0.1 equiv, 0.064 mmol, ˜8 mg) was added followed by the dropwise addition of MsCl (3 equiv, 1.93 mmol, 0.15 mL). The reaction was allowed to come to ambient temperature over 14 h at which time the reaction was quenched with sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with H2O (20 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (45% EtOAc/Hex) to afford Dimethyl 3,4-bis(8-((methylsulfonyl)oxy)octyl)hex-3-enedioate (309 mg, 0.526 mmol, 82%) as an inseparable 2:1 mixture of isomers. TLC Rf=0.24 (45% EtOAc/Hex); 1HNMR (500 MHz): δ 4.20-4.25 (ovlp. t's, 4H), 3.68 (s, 4H), 3.66 (s, 2H), 2.13 (s, 2.7H), 3.11 (s, 1.3H), 3.02 (s, 6H), 2.07-2.17 (4H), 1.71-1.79 (4H), 1.25-1.45 (20H); 13CNMR (125 MHz): δ 172.3, 172.2, 130.7, 130.6, 70.20, 70.18, 51.8, 37.6, 37.4, 37.2, 33.2, 32.8, 31.6, 29.58, 29.55, 29.33, 29.29, 29.1, 29.00, 28.97, 28.3, 28.0, 25.4; FTIR: 2929, 2855, 1732, 1435, 1350, 1170, 972, 935, 833, 721 cm−1; HRMS-ESI: calc. for C36H48NaO10S2 (M+Na)+: 607.2587. found: 607.2570.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:30][CH:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:27]([CH3:28])[CH:26]=3)=[N:21][NH:20][C:19]1=[O:29]
Reactant: Cc1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C1CCNCC1)N1C(=NNC(=O)C1C)CO2
Yield: 97 %

Procedure:
A solution of 4-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.015 g, 0.036 mmol) in DCM (6 mL) and trifluoroacetic acid (1 mL) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give 4,7-dimethyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (0.015 g, 97%). LC/MS (Table 1, Method 5) Rt=1.939 min.; MS m/z: 315 [M+H]+.