Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[S:23])[NH2:21].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[S:23])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)C)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(C)C)cc2)c1O
Yield: 72 %

Procedure:
1-[4-Hydroxy-5-(4-isopropylphenyl)-1-methyl-1H-pyrazol-3-yl]ethanone (0.116 mmol, 29.9 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.116 mmol, 24.5 mg) were stirred with dimethylformamide (2 mL) and two drops of concentrated hydrochloric acid at room temperature for 24 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (37.7 mg, yield 72%).
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=[O:8])[NH:6][C:5]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S:4]1)[CH3:2].C(C1CCNC(=O)C1)C.SC(CC)C(O)=O.N>>[CH3:2][CH2:1][C@@H:3]1[S:4][C:5]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[NH:6][C:7]1=[O:8]
Reactant: CCC1SC2(CCN(C)CC2)NC1=O
Agent: CCC(S)C(=O)O
Agent: CCC1CCNC(=O)C1
Agent: N
Product: CC[C@@H]1SC2(CCN(C)CC2)NC1=O

Procedure:
There is also provided in accordance with an embodiment of the invention a process for the preparation of 2-ethyl-8-methyl-1-thia-4,8-diaza-spiro[4.5]decan-3-one (AF267), comprising reacting 4-ethyl piperidone with 2-mercaptobutyric acid and ammonia. In an embodiment of the invention, the process further comprising obtaining the enantiomers AF267A (R-enantiomer) and AF267B (S-enantiomer) by chiral separation.
Reaction SMILES: [CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:15][C:16]3[N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]4[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:18]=4[N:17]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(Cl)Cl.O>[CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:15][C:16]3[N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]4[CH:26]=[CH:27][C:28]([CH2:30][OH:31])=[CH:29][C:18]=4[N:17]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(C(=O)O)ccc21
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a cooled (0° C.) solution of 2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid (77 mg, 0.17 mmol) and N-methyl morpholine (23 μL, 0.21 mmol) in DCM (3 mL) was added isobutyl chloroformate (27 μL, 0.21 mmol. The mixture was allowed to warm to room temperature and stirred for 2 hrs. After concentration and trituration with ethyl acetate the solid was removed by filtration and the filtrate concentrated in vacuo. The residue containing the mixed anhydride was dissolved in THF (3 mL) and added to a stirred and cooled (0° C.) solution of sodium borohydride (65 mg, 1.7 mmol) in water. The mixture was allowed to warm to room temperature and stirred for 3 hrs., followed by quenching with satd. Na/K tartrate and stirring overnight. The mixture was extracted with ethyl acetate (3×10 mL), the combined organic phases washed with brine and dried (MgSO4). Purification by flash chromatography (eluent 2%, 5% methanol in DCM) afforded 3-cyclopropyl-1-[5-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-1H-quinazoline-2,4-dione (39 mg, 52%) as a white solid.
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])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@H:24]([C:33]([NH:35][C@H:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:37][O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:34])[CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CO>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:2][C:3]([NH:23][C@H:24]([C:33]([NH:35][C@H:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:37][O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:34])[CH2:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:5]
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 86 %

Procedure:
Analogously as described in a), from Z-Gly-OSu and H-Asp(OtBu)-Ser(tBu)-OtBu there is obtained Z-Gly-Asp(OtBu)-Ser(tBu)-OtBu, yield: 86%, [α]D -6.9° (c 0.9, MeOH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>CN(C=O)C>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1cc(C)c2[nH]ccc2c1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c([N+](=O)[O-])c(C)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,7-dimethyl-4-nitro-1H-indole (CAS; 1190314-35-2, 10 g, 52.6 mmol) in DMF (200 mL) was added portionwise NaH (3.2 g, 60% in mineral oil, 79 mmol) at 0° C., and then the mixture was stirred at room temperature for 0.5 h. The mixture was cooled down to 0° C. To the red suspension was added TsCl (15.0 g, 79 mmol) at 0° C., and then the mixture was stirred at room temperature for 22 h. At this point, the reaction was quenched with half saturated aq. KHSO4 solution. The mixture was diluted with H2O, and then the whole mixture was stirred at room temperature for 1 h. The resulted solid was collected by filtration. The obtained brown solid was successively washed with H2O, MeOH, and heptane. The solid was dried to give the title compound. MS (ESI+) m/z 345.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:17](Cl)Cl)[CH:9]=2)=[CH:4][CH:3]=1.C[O-:21].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:17]=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)cc1C(Cl)Cl
Agent: [Na+]
Product: O=Cc1cc(-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h

Procedure:
4′-Chloro-3-(1,1-dichloromethyl)-4-nitrobiphenyl (0.4 g, 1.26 mmol) was dissolved in methanolic sodium methoxide (15 mL; 0.5 M). The mixture was refluxed for 12 hours under argon. The solvent was evaporated and the residue diluted in 1,4-dioxane (15 ml) and water (1 ml), then a few drops of concentrated HCl were added. The reaction mixture was stirred at 100° C. for 4 hours. The solvent was then evaporated and the crude mixture purified by flash chromatography on silica gel (eluting with dichloromethane in petroleum ether) to yield the 4′-chloro-4-nitrobiphenyl-3-carbaldehyde (0.32 g, 1.26 mmol); m/z (APCI−) 260 (40%, [M−H]−), 231 (100%). This aldehyde (0.32 g, 1.26 mmol) was dissolved in acetic acid (5 mL) and sodium perborate (0.23 g, 1.5 mmol) was added. The resulting mixture was stirred at 50° C. for 16 h. The mixture was cooled, the solvent was evaporated, ethyl acetate was added and the organic layer washed with water, dried over MgSO4 and evaporated to yield the 4′-chloro-4-nitrobiphenyl-3-carboxylic acid (0.14 g, 41%); m/z [APCI−] 276 (100%, [M−H−], 247 (60%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:31]([C:32](=[O:35])[CH2:33]Br)=[C:30]([CH2:36][CH3:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH3:40])=[C:24]([F:43])[CH:23]=1.O>CC(C)=O>[Br:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:31]([C:32](=[O:35])[CH2:33][O:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:30]([CH2:36][CH3:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH3:40])=[C:24]([F:43])[CH:23]=1
Reactant: Oc1ccccc1Oc1ccccc1
Reactant: CCCc1nc(CC)c(C(=O)CBr)n1Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1nc(CC)c(C(=O)COc2ccccc2Oc2ccccc2)n1Cc1ccc(Br)cc1F
Yield: 13 %

Procedure:
To a solution of 0.63 g (3.36 mmol) of 2-phenoxyphenol and 0.62 g (4.48 mmol) of K2CO3 in 75 mL acetone at ambient temperature was added 1.00 g (2.24 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-bromoacetyl-1H-imidazole obtained from Part B of Example 11 in 25 mL acetone. After stirring at reflux overnight, the reaction mixture was poured into water and extracted with 3×100 mL ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvents evaporated under reduced pressure. The crude product was purified by flash column chromatography using 10-40% ethyl acetate in hexane, which provided 0.16 g (6.3%) of a clear oil after evaporation of solvents under reduced pressure. 1H NMR (300 MHz, CDCl3): δ 0.95 (t, 3H, J=7.3 Hz); 1.29 (t, 3H, J =7.3 Hz); 1.66 (m, 2H); 2.60 (m, 2H); 2.81 (q, 2H, J=7.3 Hz); 5.00 (s, 2H); 6.38 (t, 1H, J=7.8 Hz); 6.89-7.29 (m, 10H). ##STR106##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)[C:21]=1[C:22](O)=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH2:16][N:15]([C:22]([C:21]4[C:25]([N:29]5[N:33]=[CH:32][CH:31]=[N:30]5)=[CH:26][CH:27]=[CH:28][C:20]=4[F:19])=[O:23])[CH2:14][CH:13]3[CH2:12]2)[N:4]=1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 45 and Intermediate 12. MS (ESI): mass calculated for C21H22FN7O3, 439.18; m/z found 440.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.89-7.80 (m, 2H), 7.73 (s, 1H), 7.53-7.43 (m, 1H), 7.15 (tdd, J=8.4, 3.7, 0.9, 1H), 5.39 (d, J=2.4, 1H), 4.02-3.48 (m, 13H), 3.31-2.89 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20]1[O:31][C:30]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=2[O:21]1>C(Cl)(Cl)Cl>[CH2:14]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][NH:8][C:6]([C:5]1[C:4]([O:18][CH3:19])=[CH:3][C:2]([NH:1][C:25]([C:24]2[CH:28]=[CH:29][C:30]3[O:31][CH2:20][O:21][C:22]=3[CH:23]=2)=[O:26])=[CH:17][CH:16]=1)=[O:7])[CH3:15]
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1OC
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)c2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
200 mg (0.75 mmol) of 4-amino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide in 10 ml of chloroform is mixed with 5 ml of 3,4-methylenedioxybenzoic acid chloride (in chloroform) and this mixture is stirred for 3 hours at room temperature. After concentration by evaporation in a vacuum, the residue is taken up in 40 ml of dilute sodium bicarbonate solution and then extracted with 40 ml of methylene chloride. The methylene chloride phase is washed with water, dried, filtered and concentrated by evaporation. The crude product, 315 mg, is taken up in methylene chloride and purified on silica gel. As a mobile solvent, a mixture that consists of methylene chloride/methanol (97:3→90:10) is used. 210 mg (67% of theory) of benzo[1,3]dioxole-5-carboxylic acid [4-(2-diethylamino-ethylcarbamoyl)-5-methoxy-phenyl]-amide (melting point 131.1° C.) is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:28])[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:26]=2)=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(O)cc2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-N-(4-hydroxyphenyl)-2-oxoacetamide (Example 199, 0.40 g, 1.05 mmol), methyl bromoacetate (0.18 g, 1.15 mmol) and potassium carbonate (0.29 g, 2.1 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 35:65) to give the title compound (0.32 g, 67%) as a colorless amorphous.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[CH3:12].ClS([N:17]=[C:18]=[O:19])(=O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[N:8]2[C:18]([NH2:17])=[O:19])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc2c(cc1F)NC(=O)C2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(cc1F)N(C(N)=O)C(=O)C2

Procedure:
Following the procedure of Example 17, the title compound was prepared from 6-fluoro-5-methyl-2-oxindole (1.0 g, 6.0 mmole) and chlorosulfonyl isocyanate (1.03 g, 7.3 mmole) in toluene (30 ml). Water (5 ml) was used for the hydrolysis step. Yield=0.58 g, 46%, m.p. 200°-203° C.
Reaction SMILES: [O:1]1[CH2:12][CH:2]1[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:1][CH:2]([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7]
Reactant: c1nc[nH]n1
Reactant: CCOP(=O)(CC1CO1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(CC(O)Cn1cncn1)OCC
Yield: 38 %

Procedure:
A mixture of diethyl 2,3-epoxypropylphosphonate (14.55 g), 1,2,4-triazole (5.18 g), potassium carbonate (10.35 g) and methyl ethyl ketone (220 ml) was heated under reflux for four hours. The supernatant liquid was decanted from a sticky residue and evaporated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (using a Waters LC 500 apparatus, silica as solid phase, and ethanol: ether in the proportion of 1:2 by volume as the liquid phase) to give diethyl 2-hydroxy-3(1,2,4-triazol-1-yl)propylphosphonate (7.5 g) as a pale yellow viscous oil. The identity of the product was confirmed by examination of its infra-red; mass; and proton, P31 and C13 nuclear magnetic resonance spectra, which were all consistent with the structure assigned.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[CH3:13][C:14]([CH3:16])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:13][C:14]1([CH3:16])[C:8]2[NH:9][C:4]3[C:5]([C:7]=2[CH2:10][CH2:11][O:12]1)=[CH:6][CH:1]=[CH:2][CH:3]=3
Reactant: CC(C)=O
Reactant: OCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)OCCc2c1[nH]c1ccccc21
Reaction time: 1.5 h

Procedure:
A solution of tryptophol (8 g, 0.05M), acetone (5 g) and p-toluenesulfonic acid (100 mg) in 100 ml of benzene containing hydrated alkali-aluminium silicate (Molecular Sieves No. 4) is heated to reflux for 1 hr. More p-toluenesulfonic acid (100 mg) and the ketone, acetone (3 g), is added and the reflux continued for a further 1.5 hr.
Reaction SMILES: ClC1C=CC=CC=1C1C=CN=CC=1N(CCS(C)(=O)=O)[C:15](=[O:30])[C:16]1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[NH2:37][C:38]1[CH:39]=[C:40]([CH:58]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:60]=1)[C:41]([N:43]([CH3:57])[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[CH3:56])=[O:42].BrCCO>>[OH:30][CH2:15][CH2:16][NH:37][C:38]1[CH:39]=[C:40]([CH:58]=[C:59]([C:61]([F:64])([F:62])[F:63])[CH:60]=1)[C:41]([N:43]([CH3:57])[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[CH3:56])=[O:42]
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(N)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Agent: OCCBr
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(NCCO)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 85, intermediate c, from 3-amino-N-methyl-N-(4-o-tolylpyridin-3-yl)-5-(trifluoromethyl)benzamide (example 164) and 2-bromoethanol after a reaction time of 48 hours at 80° C. Light yellow oil (11%). MS (ESI): m/z=430.175 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.Br[C:15]1[C:16](=[O:23])[N:17]([CH3:22])[N:18]=[C:19]([Cl:21])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:21][C:19]1[CH:20]=[C:15]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[CH:12][N:11]=2)[C:16](=[O:23])[N:17]([CH3:22])[N:18]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CN1CCC[C@H]1c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCC[C@H]1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 51.7 %

Procedure:
In a 50 mL round-bottomed flask, 5-((S)-1-methyl-pyrrolidin-2-yl)-pyridin-2-ylamine (560 mg, 3.16 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (847 mg, 3.79 mmol) and cesium carbonate (3.09 g, 9.48 mmol) were combined with dioxane (25 ml) to give a orange suspension. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (274 mg, 474 μmol, Eq: 0.15) was added followed by tris(dibenzylideneacetone)dipalladium(0) (145 mg, 158 μmol, Eq: 0.05). The reaction was degassed with argon for 10 min and heated at 95-105° C. for 4 h. No aniline starting material remained. The reaction mixture was diluted with 200 ml CH2Cl2. MgSO4 was added and the mixture was stirred for 5 min. The reaction was filtered and the filtercake was washed several times with CH2Cl2. The combined filtrate and washes were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 1% to 2% MeOH in CH2Cl2) to afford the desired product (522 mg, 52%). (M+H)+=320 m/e.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[CH:10]([CH3:11])[C:6]=2[C:5]([F:24])=[C:4](Cl)[N:3]=1.[NH2:26][C@@H:27]1[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]1[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[CH:10]([CH3:11])[C:6]=2[C:5]([F:24])=[C:4]([NH:26][C@@H:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[N:3]=1
Reactant: COc1ccc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2C)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)c3c(Cl)nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2C)c(OC)c1
Temperature: 95 °C
Yield: 0 %

Procedure:
To a sealed tube was added 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1-methyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (430 mg, 1.12 mol), tert-butyl ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate (7.5 g, 34.2 mol), and DIPEA (0.97 mL, 5.58 mmol). The mixture was heated in the sealed tube at 95° C. for 72 h. The mixture was purified via preparative HPLC to give the title compound as a yellow solid (100 mg, 16%). [M+H] calc'd for C27H34ClFN4O6, 565. found, 565.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH:17]([CH2:51][O:52]CC1C=CC=CC=1)[CH2:18][N:19]([CH2:47][C:48]([OH:50])=[O:49])[CH2:20][CH:21]([CH2:38][O:39]CC1C=CC=CC=1)[N:22]([CH2:34][C:35]([OH:37])=[O:36])[CH2:23][CH2:24][CH2:25][O:26]CC1C=CC=CC=1)[CH2:6][CH2:7][CH2:8][O:9]CC1C=CC=CC=1)([OH:3])=[O:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:35]([CH2:34][N:22]([CH:21]([CH2:38][OH:39])[CH2:20][N:19]([CH2:47][C:48]([OH:50])=[O:49])[CH2:18][CH:17]([CH2:51][OH:52])[N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:6][CH2:7][CH2:8][OH:9])[CH2:23][CH2:24][CH2:25][OH:26])([OH:37])=[O:36]
Reactant: O=C(O)CN(CC(COCc1ccccc1)N(CCCOCc1ccccc1)CC(=O)O)CC(COCc1ccccc1)N(CCCOCc1ccccc1)CC(=O)O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(O)CN(CC(CO)N(CCCO)CC(=O)O)CC(CO)N(CCCO)CC(=O)O
Reaction time: 16 h

Procedure:
N4,N7,N10 -Triscarboxymethyl-1,13-bisbenzyloxy-5,9-bisbenzyloxymethyl-4,7,10-triazatridecane (0.30 g, 0.4 mmol) was dissolved in methanol (15 ml), 10% Palladium on carbon (0.3 g) and ammonium formate (0.1 g) were added and the mixture was kept at 0° C. for 16 hours. The catalyst was filtered off and washed with methanol (5 ml). The filtrate was evaporated and the title compound was isolated. as a white powder. Yield 0.14 g (95%). M.p. 173°-177° C. The structure was confirmed by 1H NMR and 13CNMR.