Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCBr
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCSc1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorothiophenol (5.04 g, 28.2 mmol), caesium carbonate (10.1 g, 31 mmol) and ethyl 3-bromopropanoate (4.2 mL, 33 mmol) in acetone (100 mL) were refluxed overnight under N2(g). After filtration and concentration under reduced pressure, the residue was partitioned between dichloromethane and water. After separation, the aqueous phase was extracted once with dichloromethane. Drying and removal of the solvent in vacuo afforded a liquid residue that contained ˜30% (HPLC) of unreacted 2,4-dichlorothiophenol. The mixture was refluxed again with caesium carbonate (4.7 g) and ethyl 3-bromopropanoate (2 mL) in acetonitrile (100 mL) under N2(g) for 2 h. After filtration and concentration under reduced pressure, the residue was dissolved in diethyl ether and washed with 2 M aq. sodium hydroxide and water. Drying and removal of the solvent in vacuo afforded the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH3:22])[C:19]([NH2:21])=O)[C:11]3=[O:23])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH3:22])[C:19]([NH2:21])=[S:35])[C:11]3=[O:23])=[CH:4][CH:3]=1
Reactant: C[C@@H](C(N)=O)N1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: C[C@@H](C(N)=S)N1C(=O)c2ccc(OCc3ccc(F)cc3)cc2C1=O
Reaction time: 72 h
Yield: 36.3 %

Procedure:
A mixture of (S)-2-[5-(4-fluoro-benzyloxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-propionamide (171 mg, 0.5 mmol) and Lawesson's reagent (243 mg, 0.6 mmol) in tetrahydrofuran (20 mL) was stirrred at room temperature for 72 h. Then the mixture was evaporated and the residue was purified by chromatography (SiO2, CH2Cl2: 2N NH3/MeOH 99:1 to 19:1) to afford the title compound (65 mg, 36%) as an off-white solid after recrystallisation from MeOH. MS: m/e=359.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl[CH:11]([F:13])[F:12]>CC(O)C.[OH-].[K+].O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([F:13])[F:12])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: FC(F)Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a tared, sealed 350 mL round-bottomed pressure flask containing a solution of 3,5-dibromophenol (10.0 g, 39.7 mmol; see Example 27(ii) above) in 2-propanol (100 mL) and 30% KOH (80 mL) at −78° C. was added chlorodifluoromethane via bubbling for 15 min through the septum. The septum was replaced with a Teflon stopper and the flask was then sealed and allowed to warm to room temperature where the flask was weighed and determined to contain 12.0 g (138 mmol) of chlorodifluoromethane. The solution was refluxed overnight in an oil bath set at 80° C. The flask was cooled to room temperature, the pressure cautiously released and the contents diluted with H2O (200 mL). The aqueous layer was extracted with CHCl3 (2× 150 mL), then the combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Kugelrohr distillation at 80° C. at 0.2 mm Hg to afford the sub-title compound (9.6 g, 80%) as clear liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10][CH:9]1[C:17]([O-:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][C:17]([CH:9]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1)=[O:19]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (589 mg, 2.18 mmol, Eq: 1.00) and 2,6-difluoroaniline (480 mg, 0.4 mL, 3.72 mmol, Eq: 1.71) in pyridine (7 mL) (ice-bath) was added dropwise phosphoryl trichloride (660 mg, 0.4 mL, 4.3 mmol, Eq: 1.97). The cooling bath was removed and the resulting yellow/orange suspension was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with water (20 mL). The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (1×5 mL). The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 100% EtOAc in DCM/hexanes (1:1)). After the combined fractions were concentrated, the off-white solid was treated with 5% MeOH/ether (˜10 mL) to give tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate as a white solid (532 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[F:18][C:19]([F:30])([F:29])[C:20]1[C:25]([CH:26]=[CH2:27])=[CH:24][N:23]=[C:22]([CH3:28])[CH:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:30][C:19]([F:18])([F:29])[C:20]1[CH:21]=[C:22]([CH3:28])[N:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:9]1[C:10]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[C:7]2[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:8]1=2
Reactant: C=Cc1cnc(C)cc1C(F)(F)F
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cc(C(F)(F)F)c(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-isopropyl-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH3:25][N:26]([CH3:42])[C:27]1[N:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:30]5[CH:29]=[N:28][C:27]([N:26]([CH3:42])[CH3:25])=[N:32][CH:31]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnc(N(C)C)nc4)cc2OCC3)n(C(C)C)n1

Procedure:
8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with Dimethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine to give 245. MS(ESI+) 431.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]2[CH:11]([C:12]#[N:13])[CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1.[NH2:14][C:15]1[C:20]2[CH:21]=[C:22](Br)[S:23][C:19]=2[C:18]([C:25]([NH2:27])=[O:26])=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[CH:21]=[C:22]([C:2]3[CH:3]=[C:4]([CH:7]4[CH:11]([C:12]#[N:13])[CH2:10][CH2:9][O:8]4)[S:5][CH:6]=3)[S:23][C:19]=2[C:18]([C:25]([NH2:27])=[O:26])=[CH:17][N:16]=1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Reactant: N#CC1CCOC1c1cc(Br)cs1
Product: N#CC1CCOC1c1cc(-c2cc3c(N)ncc(C(N)=O)c3s2)cs1

Procedure:
87 was prepared from 2-(4-bromo-thiophen-2-yl)tetrahydro-furan-3-carbonitrile 86 and 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 in a similar manner to that described in Example 18. 1H NMR (400 MHz, d6-DMSO) δ: 8.48 (s, 1H), 7.90 (bs, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.26 (bs, 1H), 7.12 (s, 2H), 5.30 (d, J=7.49 Hz, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 3.44 (m, 1H), 2.49 (m, 1H), 2.33 (m, 1H). MS (EI) m/z (M+H+) 371.
Reaction SMILES: N12CCCCC1C=NCCC2.[CH2:12]([N:19]([CH2:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:20](=[O:25])[C@@H:21](Br)[CH2:22][OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl.P([O-])([O-])([O-])=O>O1CCCC1>[CH2:12]([N:19]([CH2:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:20](=[O:25])[C@@H:21]1[O:23][CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)S(=O)(=O)CN(Cc1ccccc1)C(=O)[C@@H](Br)CO
Agent: C1=NCCCN2CCCCC12
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)CN(Cc1ccccc1)C(=O)[C@H]1CO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.125 g (7.4 mmol) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added at 0° to a solution of 118 g (3 mmol) of N-benzyl-N-tert.-butylsulphonylmethyl-2-(S)-bromo-3-hydroxypropionic acid amide (see Example 4) in 15 ml of absolute tetrahydrofuran and the whole is stirred for a further 90 minutes at room temperature. After working up with methylene chloride and phosphate buffer having a pH of 7.0, the crude product obtained from the organic phase is chromatographed over 50 g of silica gel. After eluting with a mixture of ethyl acetate/toluene (1:1), the pure title compound, identical to the compound according to Example 6, is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17][OH:18])[CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O

Procedure:
A solution of trans-{1-[2-(4-fluorophenyl)ethyl]-4-methylpiperidin-3-yl}-methanol (251 mg, 1.0 mmol) in dichloromethane (10 mL) was treated with triethylamine (280 μL, 2.0 mmol) and stirred on an ice-acetone bath. Methanesulfonyl chloride (85 μL, 1.1 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 1.5 hours. The solution was concentrated under vacuum, and the residue was taken up in ethyl acetate and filtered. The filtrate was concentrated under vacuum to provide an orange gum (342 mg, quantitative) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.98 (t, J=9 Hz, 2H), 4.30 (dd, J=10, 3 Hz, 1H), 4.18 (dd, J=10, 7 Hz, 1H), 3.13 (dm, J=10 Hz, 1H), 3.02 (s+m, 4H), 2.83 (m, 2H), 2.66 (m, 2H), 2.07 (m, 2H), 1.76 (m, 2H), 1.43 (m, 2H), 1.02 (d, J=6, 3H).
Reaction SMILES: O[CH:2]([CH2:12][O:13][CH3:14])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].CCN(S(F)(F)[F:21])CC.C(O)C>O1CCOCC1>[F:21][CH:2]([CH2:12][O:13][CH3:14])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: CCN(CC)S(F)(F)F
Reactant: COCC(O)Cn1ccnc1[N+](=O)[O-]
Solvent: CCO
Solvent: C1COCCO1
Product: COCC(F)Cn1ccnc1[N+](=O)[O-]
Yield: 52 %

Procedure:
To a solution of 914 mg (4.54 mmol) of 1-(2'-hydroxy-3'-methoxypropyl)-2-nitroimidazole in 5.0 ml of dry dioxane, 1.00 g (6.20 mmol) of DAST was dropwise added with cooling by ice and then reacted for 2 hours at room temperature with stirring. After reaction, to the solution, 5.0 ml of ethanol was added to decompose excess DAST. The solution was then concentrated and subjected to isolation and purification by silica gel column chromatography to give 480 mg of 1-(2-'-fluoro-3'-methoxypropyl)-2-nitroimidazole.
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[O:18]=[C:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O1C2C=CC(O)=CC=2OC1.[CH2:45]1[C:53]2[C:48](=[CH:49][C:50]([OH:54])=[CH:51][CH:52]=2)[CH2:47][CH2:46]1>>[OH:28][C:27]1([C:51]2[CH:52]=[C:53]3[C:48](=[CH:49][C:50]=2[OH:54])[CH2:47][CH2:46][CH2:45]3)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]1=[O:18]
Reactant: CCOC(=O)CN1C(=O)C(=O)c2ccccc21
Reactant: Oc1ccc2c(c1)CCC2
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 10, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 5-indanol, the title compound was obtained (84%): 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 7.55 (d, 1H), 7.38 (td, 1H), 7.20 (t, 1H), 6.9 (s, 1H), 6.80 (d, 1H), 6.65 (s, 1H), 4.45 (ABq, 2H), 4.32-4.25 (br, 1H), 4.20 (q, 2H), 2.83 (t, 2H), 2.74-2.65 (m, 2H), 2.06-1.94 (m, 2H), 1.27 (t, 3H); MS (ES+) m/z 350 (M−17), 390 (M+23).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][C:17]([CH3:24])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH2:55]([O:62][NH2:63])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH2:55]([O:62][NH:63][C:12](=[O:14])[CH2:11][C@H:10]([C:15]1[O:16][C:17]([CH3:24])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)O)oc1C
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[4-(methoxycarbonyl)-5-methyl-1,3-oxazol-2-yl]hexanoic acid (Preparation 70) (2.48 g, 7.36 mmol) was cooled to 0° and treated with 1-hydroxybenzotriazole hydrate (994 mg, 7.36 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.12 g, 11.06 mmol) and N-methylmorpholine (1.21 ml, 11.04 mmol). The mixture was stirred for 15 minutes then treated with O-benzylhydroxyamine (1.17 g, 7.36 mmol) and further N-methylmorpholine (0.81 ml, 7.36 mmol). The mixture was stirred for 1 hour being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed sequentially with water, a saturated solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a colourless oil (3.22 g)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.ClC1C=CC([N+]([O-])=O)=CC=1O>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Brc1cccnc1
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Product: Brc1ccc(-c2cccnc2)cc1

Procedure:
The title compound was prepared from 3-bromopyridine (5 g) and 4-bromophenylboronic acid by the method described in Description 15 (2.6 g, 35%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25]3[N:30]=[C:29]([C:31]4[CH:32]=[N+:33]([O-:37])[CH:34]=[CH:35][CH:36]=4)[CH:28]=[CH:27][N:26]=3)[CH:18]=2)=[O:15])=[CH:12][CH:11]=1.C(OCC)(=O)C>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25]4[N:30]=[C:29]([C:31]5[CH:32]=[N+:33]([O-:37])[CH:34]=[CH:35][CH:36]=5)[CH:28]=[CH:27][N:26]=4)[CH:18]=3)=[O:15])=[CH:38][CH:39]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2ccc[n+]([O-])c2)n1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2ccc[n+]([O-])c2)n1
Temperature: 10 °C
Reaction time: 15 h

Procedure:
N-Methylpiperazine (99 mg, 1.0 mmol) is added to a stirred suspension of 4-chloromethyl-N-[4-methyl-3-[[4-(1-oxido-3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl]-benzamide (220 mg, 0.49 mmol) In ethanol (5 mL). The mixture is then stirred at 10° C. for 15 h to give a solution, which is then cooled to RT and treated with ethyl acetate (200 mL). The resulting solution is washed with aqueous sodium hydroxide (100 mL of 2M) and saturated aqueous sodium chloride solution (100 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 25% aqueous ammonia-methanol-dichloromethane (0.5:10:90) to give the title compound as a yellow crystalline solid, m.p. 232-235° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CN1CCOCC1.[N:13]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=[O:24])=[O:20]>C(Cl)Cl>[N:13]1([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:24])=[O:20]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: NCC(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Two solutions were prepared before the peptide coupling. Solution A: H-Gly-OH (1.2 eq.) was dissolved in MSA (3.0 eq.) at maximum 60° C. The suspension was cooled down to 25° C., diluted with DCM and stirred for at least 8 hours before being cooled to −15° C. In solution B, the carboxylic function of the Z-Glp-Pro-OH was dissolved with DCM and NMM (1.05 eq.). The solution was cooled to −15° C. The carboxylic acid was activated with IBCF (1.05 eq.) and the silylated solution A was then added to the slurry. The slurry was stirred for at least 0.5 h and left to warm to 25° C. The mixture was quenched with water and the addition of a solution of KHSO4 under stirring precipitated the peptide. The solid was filtered and washed with water. After drying under vacuum, 80% of Z-Glp-Pro-Gly-OH was recovered.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=2[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][NH2:31].C(O)C>CO>[C:1]1([S:7]([CH2:10][C:11]2[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=2[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:30][NH2:31])=[O:22])[CH2:16][CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccccc2CS(=O)(=O)c2ccccc2)CC1
Solvent: CCO
Solvent: CO
Product: NNC(=O)CN1CCN(Cc2ccccc2CS(=O)(=O)c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{29} (1.16 g, 2.77 mmol, 1 equiv.), anhydrous hydrazine (0.26 mL, 8.32 mmol, 3 equiv.), ethanol (15.6 mL), methanol (10 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{29} (0.88 g, 79%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.10 (br s, 1H), 7.66 (dd, 2H, J=0.5, 8.0 Hz), 7.64-7.61 (m, 1H), 7.47 (t, 2H, J=8.0 Hz), 7.24 (dt, 1H, J=1.0, 7.5 Hz), 7.17-7.12 (m, 2H), 6.95 (d, 1H, J=7.5 Hz), 4.80 (s, 2H), 3.83 (br s, 2H), 3.40 (s, 2H), 3.04 (s, 2H), 2.47 (br s, 4H), 2.35 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 138.6, 138.0, 133.7, 132.6, 131.1, 128.9, 128.7, 128.5, 128.0, 127.5, 61.1, 60.5, 59.1, 53.6, 53.0.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH:12]4[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:24].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH:12]4[CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][C:23]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[O:24])[CH2:15][CH2:14][CH:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CN1CCN2c3c(cccc31)C1CCNCCC12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCN2c3c(cccc31)C1CCN(CCCC(=O)c3ccc(F)cc3)CCC12
Temperature: 96 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
3-Methyl-2,3,7,8,9,10,11,11a-octahydro-1H,6bH-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline (72 mg, 0.3 mmol), 4-chloro-4′-flourobutyrophenone (119 mg, 0.6 mmol), KI (49 mg, 0.3 mmol), and DIEA (383 mg, 3 mmol) were added to dioxane (2.5 mL). The suspension was stirred at 96° C. for 18 hrs. The reaction was cooled to rt and then concentrated. The residue was purified by column chromatography (5-10 % MeOH/CH2Cl2), to afford the title compound (37.5 mg, 31%) as an oil. The enantiomers of the title compound were separated on a Chiracel OD column using 8% EtOH-Hexane as the eluent. 1H NMR (CDCl3, 300 MHz) δ 7.9-8.1 (2H, m), 7.1-7.2 (2H, m), 6.6-6.7 (1H, m), 6.3-6.5 (2H, m), 2.7-3.8 (19 H, m), 1.9-2.3 (4H, m) ppm. MS (ESI): 408.3 (base, M+H)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.ClCCl.C1(N=C=NC2CCCCC2)CCCCC1.C(OC([N:39]1[C:43]([CH:44]2[CH2:46][CH2:45]2)=[CH:42][C:41]([NH2:47])=[N:40]1)=O)(C)(C)C>C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:47][C:41]3[NH:40][N:39]=[C:43]([CH:44]4[CH2:46][CH2:45]4)[CH:42]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Cc1ccc2c(c1)OCO2)Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.7 %

Procedure:
To a solution of 96.8 mg (0.537 mmol) of 2-(1,3-benzodioxol-5-yl)-acetic acid in 3 ml of dichloromethane 360 mg (0.720 mmol) of polystyrene supported dicyclohexylcarbodiimide (loading=2 mmol/g) and 40 mg (0.179 mmol) of tert-butyl-3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate were added. The mixture was maintained under stirring at room temperature for 96 hours and after that time filtered, washed several times with dichloromethane and evaporated to dryness. The residue was re-dissolved with 3 ml of trifluoroacetic acid 10% V/V in dichloromethane and maintained at room temperature for an hour. The solvent was then evaporated, the residue re-dissolved in dichloromethane and washed with a saturated solution of sodium hydrogenocarbonate. The organic layer was evaporated to dryness to give, after trituration with diethylether, 32 mg (63% yield) of the title compound.
Reaction SMILES: C[O-].[CH3:3][O:4][C:5](=O)[CH:6]=[O:7].[CH:9]1([NH:15][C:16]([NH2:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)(=O)C>CO>[CH3:3][O:4][CH:5]1[NH:18][C:16](=[O:17])[N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]1=[O:7]
Reactant: NC(=O)NC1CCCCC1
Reactant: COC(=O)C=O
Agent: C[O-]
Solvent: CO
Solvent: CC(=O)O
Product: COC1NC(=O)N(C2CCCCC2)C1=O
Yield: 31.4 %

Procedure:
750 mg of glyoxylic acid methyl ester methyl alcoholate and 920 mg of N-cyclohexylurea were refluxed in 50 ml of a mixture of acetic acid and methanol (4:1) for 1 hour. After cooling, the solvent was removed by distillation and the residue was purified by column chromatography on silica gel. The obtained crude product was recrystallized from benzene to give 420 mg of 5-methoxy-3-cyclohexylhydantoin (compound 20) in the form of colorless needle crystals.