Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[C:10]([CH3:29])=[N:11][C:12]3[C:17]([N:18]=2)=[C:16]([C:19]2[NH:23][C:22]4[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=4[CH:20]=2)[CH:15]=[CH:14][CH:13]=3)[CH2:3]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][C:10]1[C:9]([NH:8][C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:3]2)=[N:18][C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]1[NH:23][C:22]2[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=2[CH:20]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](NS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 9.8 %

Procedure:
A mixture of (R)-2-(3-(((1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483, 52 mg, 0.133 mmol), methanesulfonyl chloride (41.4 μL, 0.533 mmol), and triethylamine (74.2 μL, 0.533 mmol) in DCM (1.33 mL) was stirred at 0° C. for 5 min; the reaction mixture was warmed to RT and stir for 1 h when product was observed via LCMS. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-5% 2 M ammonia in MeOH/DCM to give N-((1R,3S)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinoxalin-2-yl)amino)cyclohexyl)methanesulfonamide (489, 6 mg, 0.013 mmol, 10% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.36 (m, 2H) 1.37-1.51 (m, 2H) 1.59 (d, J=6.65 Hz, 3H) 1.99-2.06 (m, 1H) 2.16-2.23 (m, 1H) 2.39 (d, J=11.15 Hz, 1H) 2.52-2.57 (m, 1H) 2.59 (s, 3H) 3.00 (s, 3H) 3.48-3.59 (m, 1H) 3.99-4.10 (m, 1H) 4.54 (d, J=7.04 Hz, 1H) 4.68 (q, J=6.98 Hz, 1H) 4.97 (d, J=6.65 Hz, 1H) 5.68 (s, 1H) 6.92 (d, J=1.37 Hz, 1H) 7.42 (t, J=7.82 Hz, 1H) 7.69-7.74 (m, 1H) 7.91-7.97 (m, 1H) 12.29 (br. s., 1H). MS (ESI, pos. ion) m/z: 469.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2[C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:29]2[C:28]3[O:24][CH2:25][CH2:26][C:27]=3[CH:32]=[CH:31][CH:30]=2)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCC3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-Dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=494.3.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[C@@H:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=4[CH:34]=3)[CH2:16][N:15]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C@@H:14]([CH2:45][C:46]([OH:48])=[O:47])[CH2:13]2)=[CH:8][CH:7]=1>CCOCC.CO>[CH3:3][O:47][C:46](=[O:48])[CH2:45][C@H:14]1[CH2:13][C@H:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=2)[C@@H:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]3[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:24]=3[CH:34]=2)[CH2:16][N:15]1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:36])=[O:37]
Reactant: C=[N+]=[N-]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Solvent: CCOCC
Solvent: CO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 3.5 h

Procedure:
4 ml of a solution of diazomethane in ether (0.2M) are added dropwise to a solution of 0.12 g of [(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (from example 25f) in 2 ml of methanol at 0° C. The reaction mixture is worked up after 3.5 hours by quenching with solid magnesium sulfate to decompose any excess diazomethane, filtering and concentrating under reduced pressure to afford the crude title compound as a pale yellow solid with was used in the next step without any further purification. Rf=0.78 (EtOAc); Rt=5.26.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.C(O)C.Cl[Pd]Cl>[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C@@H:14]4[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]4)[C:9]4[C:4](=[N:5][CH:6]=[CH:7][N:8]=4)[CH:3]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
A mixture of (S)-tert-butyl 3-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)piperidine-1-carboxylate (0.15 mmol), 4-morpholinophenylboronic acid (0.23 mmol), PdCl2 (dppf) (0.015 mmol) and Cs2CO3 (0.30 mmol) in dimethoxyethane/ethanol was sealed in a microwave reaction and stirred at 160° C. for 45 minutes in a microwave reactor. The mixture was cooled to room temperature, concentrated, and purified by chromatography to afford the title compound (73% yield). MS (m/z): 505 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17]([O:20][CH2:21][CH2:22]O)[C:18]#[CH:19].C(N(CC)CC)C>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16][CH2:22][CH2:21][O:20][CH2:17][C:18]#[CH:19])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C#CCOCCO
Reactant: O=C(O)COc1ccc(Cl)c2cccnc12
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CCOCCOC(=O)COc1ccc(Cl)c2cccnc12
Yield: 16.4 %

Procedure:
5.0 g (0.021 mol) of 5-chloroquinolin-8-oxyacetic acid are heated at 70° C. in 70 ml of thionyl chloride for one hour. The excess thionyl chloride is then distilled off in vacuo and the residue is suspended in 150 ml of carbon tetrachloride. 2.10 g (0.021 mol) of 2-propargyloxyethanol are added dropwise to this suspension, 2.30 g (0.023 mol) of triethylamine are then added dropwise and the mixture is heated under reflux for 12 hours. The suspension is then washed with in each case 70 ml of 2N HCl and 5 percent strength sodium hydroxide solution, the organic phase is dried over magnesium sulfate and the solvent is stripped off in vacuo. The residue is recrystallized from n-heptane. 1.1 g (16.3% of theory) of 2-(propargyloxy)ethyl 5-chloroquinolin-8-oxyacetate of melting point 53° C. are thus obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH3:21])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([N:9]=[N:10][C:11]([N:1]=[N+:2]=[N-:3])([CH3:21])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])([CH3:8])([CH3:7])[CH3:6]
Reactant: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: CCCCOC(=O)CCC(C)(N=NC(C)(C)C)N=[N+]=[N-]
Temperature: 15 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 20.2 grams (0.31 moles) of sodium azide in 200 ml. of 70% aqueous methanol cooled in an ice bath, was added dropwise 80.0 grams (.29 moles) of n-butyl 4-t-butylazo-4-chlorovalerate (prepared as in Example XX) over a 20 minute period. After the addition was complete the reaction mixture was stirred for 1 hour at 15° C. It was then poured into 500 ml. of water and extracted with pentane. The pentane solution was washed with water, saturated NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated to leave 77 grams (93.7% yield) of the desired product.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]([CH3:13])[C:7]=1[C:8](=[O:12])SCC)#[N:2].C([SiH](CC)CC)C>CC(C)=O.[Pd]>[CH:8]([C:7]1[N:6]([CH3:13])[CH:5]=[N:4][C:3]=1[C:1]#[N:2])=[O:12]
Reactant: CCSC(=O)c1c(C#N)ncn1C
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CC(C)=O
Product: Cn1cnc(C#N)c1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
In a 750 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, S-ethyl 4-cyano-1-methyl-1H-imidazole-5-carbothioate x85 (8 g, 0.041 mol) is dissolved in 400 ml of acetone. Pd on charcoal (1.6 g) is added and the mixture is cooled to 0° C. Triethylsilane (13.1 ml, 0.082 mol) is added dropwise and the mixture is stirred at 0° C. for 0.5 h. The reaction is monitored by NMR. Three additional portions of triethylsilane (0.041 mol, 0.041 mol and 0.0205 mol) are added over a period of 14 h, 17 h and 19 h respectively while stirring at 0° C. The mixture is filtered on Celite after complete consumption of starting product. The solvent is evaporated and the residue is purified twice by chromatography on silicagel (Hexane/AcOEt: 6/4 (v/v)) to afford 3 g of 5-formyl-1-methyl-1H-imidazole-4-carbonitrile x86.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[CH:40]=[CH:39][C:11]2[O:12][C:13]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)=O)=[CH:14][O:15][C:10]=2[CH:9]=1>C(OCC)C>[OH:7][C:8]1[CH:40]=[CH:39][C:11]2[O:12][C:13]([CH2:16][N:18]3[CH2:19][CH2:20][N:21]([CH:24]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[CH2:22][CH2:23]3)=[CH:14][O:15][C:10]=2[CH:9]=1
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Oc1ccc2c(c1)OC=C(CN1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, heat at reflux for 3 hours, in the presence of 5 mmol of lithium aluminium hydride, a solution of 2 mmol of 6-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin in 35 cm3 of diethyl ether. After cooling, hydrolysis, removal of the insoluble mineral compounds by filtration and drying over magnesium sulfate, the compound obtained is purified by chromatography on a column of silica (eluant: petroleum ether/ethyl acetate, 40:60). 6-Hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylmethyl}-1,4-benzodioxin is thereby obtained in a yield of 85%. Melting point: 190° C. ##STR79##
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:52]=[CH:51][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38][C:37]3=[O:44])=[O:33])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[O:53]1[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]1>>[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][N:48]([CH:56]5[CH2:57][CH2:58][O:53][CH2:54][CH2:55]5)[CH2:47][CH2:46]4)[C:37](=[O:44])[NH:38][C:39](=[O:43])[NH:40][C:41]3=[O:42])=[O:33])=[CH:51][CH:52]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(C4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(C4CCN(C5CCOCC5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 22 %

Procedure:
Following the procedure analogous to that used in reaction (9), the compound from Example 29 was reacted with tetrahydro-4H-pyran-4-one for 5 days to provide the title compound (5 mg, 22%). MS found: (M+H)+=600.4.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([F:36])[CH:27]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:24][C:20]2[CH:21]=[N:22][CH:23]=[C:18]([C:16]3[CH:15]=[CH:14][C:10]4[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:9]=4[N:17]=3)[CH:19]=2)(=[O:33])=[O:34])=[C:28]([F:36])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 4-chloro-2-fluorobenzene-1-sulfonyl chloride (0.043 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 4-chloro-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.034 g, 43%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.71 (1H, m), 7.24 (1H, d, J=8.4 Hz), 7.86-7.90 (1H, m), 8.24 (1H, d, J=8.8 Hz), 8.39 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=7.6 Hz), 8.85 (1H, s), 9.19 (1H, s). m/z=516.1 [M+1]+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23]([NH:25][CH2:26][C:27]1([NH:32][C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:24])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[C:36]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:35]=[CH:34][C:33]([NH:32][C:27]2([CH2:26][NH:25][C:23]([NH:22][C:14]3[C:13]([CH:10]([CH3:12])[CH3:11])=[CH:18][CH:17]=[CH:16][C:15]=3[CH:19]([CH3:21])[CH3:20])=[O:24])[CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(Nc2ccc(I)cc2)CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(Nc2ccc(-c3ccccc3)cc2)CCCC1
Temperature: 100 °C
Reaction time: 240 h
Yield: 57.3 %

Procedure:
45 mg (0.37 mmol) of phenylboronic acid are added to 150 mg (0.29 mmol) of 1-(2,6-diisopropylphenyl)-3-[1-(4-iodophenylamino)-cyclopentylmethyl]-urea (Example 6d) in 20 ml of toluene. 370 μl (0.74 mmol) of a 2M aqueous solution of potassium carbonate are added. The reaction medium is degassed with nitrogen for 20 min, then 10 mg (8.65 μmol) of tetrakis-(triphenylphosphine)palladium are added. The medium is heated at 100° C. for 6 hours, then at ambient temperature for 10 days. It is then poured into water and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated and the residue is chromatographed on silica gel (heptane/ethyl acetate, 80/20 v/v). 78 mg of 1-[1-(biphenyl-4-ylamino)cyclopentylmethyl]-3-(2,6-diisopropyl-phenyl)-urea are obtained in the form of a white solid. (M.Pt.=198° C., Yield=57%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].[C:11](=O)([O:37]C1C=CC=CC=1)[O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[N:23]=[C:22]2[CH2:35][CH3:36])=[CH:17][CH:16]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[O:37])[O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]3[CH:26]=[C:27]([Cl:34])[C:28]([C:30]([F:31])([F:33])[F:32])=[CH:29][C:24]=3[N:23]=[C:22]2[CH2:35][CH3:36])=[CH:19][CH:20]=1)(=[O:9])=[O:8]
Reactant: NS(=O)(=O)c1ccccn1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-pyridinesulfonamide (Naito, T.; et al., Chem. Pharm. Bull., 1955, 3, 38) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 243).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:14])[C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[O:6].[BH4-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:14])[C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)Oc1c(F)cc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1c(F)cc(CO)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3,5-difluoro-4-isopropoxy-benzaldehyde (0.14 g) in EtOH (10 ml) is added NaBH4 (60.7 mg; 1.61 mmol) at 10° C. in 5 portions. The mixture is slowly warmed to RT and stirred for 3 h. After aqueous work-up (3,5-difluoro-4-isopropoxy-phenyl)-methanol is obtained which is directly chlorinated using SOCl2 (1 ml; 13.8 mmol) in CH2Cl2 (10 ml) at RT for 3 h. After aqueous work-up 5-chloromethyl-1,3-difluoro-2-isopropoxy-benzene (0.14 g) is obtained as a yellow oil which is used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N1CCOCC1)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCCc1ccccc1
Agent: CCN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
17.6 Grams of a 50% solution of n-propane-phosphonic acid anhydride in methylene chloride are added in 3 portions, with stirring and the exclusion of moisture, to a solution of 2.4 g of β-phenylethylamine, 2.2 g of benzoic acid and 14 ml of N-ethyl morpholine in 25 ml of methylene chloride. The temperature rises to about +40° C. The mixture is cooled to room temperature, while stirring, and is worked up after 24 hours of standing by adding 350 ml of methylene chloride and extracting the solution three times with 50 ml each of water, saturated sodium carbonate solution and potassium bisulfate solution. The crude product crystallizes from the methylene chloride solution dried over magnesium sulfate. Said product is filtered off with suction together with a small amount of petroleum ether (boiling point 40° to 60° C.).
Reaction SMILES: [C:1]([O:5][C:6](=O)[CH2:7][NH:8][CH2:9][CH:10](OC)OC)([CH3:4])([CH3:3])[CH3:2].C([O:23][C:24]([NH:26][C@H:27]([C:34]([OH:36])=[O:35])COC(C)(C)C)=O)C1C=CC=CC=1>>[C:1]([O:5][CH2:6][C@@H:7]1[NH:8][CH2:9][CH2:10][N:26]([CH2:27][C:34]([OH:36])=[O:35])[C:24]1=[O:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(CNCC(=O)OC(C)(C)C)OC
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC[C@@H]1NCCN(CC(=O)O)C1=O

Procedure:
In substantially the same manner as in Reference Example 2, the title compound was synthesized from N(2,2-dimethoxyethyl) glycine tert-butyl ester and N-benzyloxycarbonyl-O-tert-butyl-L-serine. M.p. 178°-180° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](O)(=[O:37])[C@H:34]([CH3:36])[OH:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[C@@H:34]([OH:35])[CH3:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)[C@H](C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.4 %

Procedure:
To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.23 mmol), L-lactic acid (23 mg, 0.25 mmol) and DIPEA (45 μL, 0.25 mmol) in DCM (2 mL) was added HATU (96 mg, 0.25 mmol). The resulting yellow mixture was stirred for 2.5 h at r.t. then partitioned between DCM and H2O. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 20-35%) affording 718 as a white solid (19 mg, 16%). LCMS (method I): RT 2.92 min, [M+H]+ 505.2. 1H NMR (CDCl3, 400 MHz): δ 7.98-7.97 (1 H, m), 7.90-7.80 (1 H, m), 7.40-7.30 (2 H, m), 4.33-4.32 (7 H, m), 4.01-4.00 (1 H, m), 3.86-3.85 (5 H, m), 3.77 (3 H, d, J=1.96 Hz), 3.50-3.35 (4 H, m), 3.19-3.17 (2 H, m), 1.48 (3 H, t, J=7.42 Hz), 1.34 (3 H, dd, J=6.69, 4.73 Hz),
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[OH:14][C@H:15]1[CH2:19][CH2:18][NH:17][C@H:16]1[CH3:20].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C@H:16]1[CH3:20]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C[C@@H]1NCC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](O)CCN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 4-fluoro-2-(trifluoromethyl)benzonitrile (851 mg), (2S,3S)-3-hydroxy-2-methylpyrrolidine (5 mmol) and lithium carbonate (665 mg), the title compound was obtained as a colorless solid (yield: 630 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][C@@H:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][OH:25].C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][C@@H:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][OH:25])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H](CO)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (0.166 g, 0.49 mmol), (S)-(−)-2-amino-3-phenyl-1-propanol (0.091 g, 0.6 mmol), sodium cyanoborohydride (0.062 g, 1.0 mmol), and acetic acid (1 drop) were combined in CH2Cl2 (10 mL) and stirred overnight at room temperature. After aqueous work-up, the crude material was used directly in the next step.