Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[OH:20])/[NH2:18])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CC[O:25][CH2:24]C1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(O)=O>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2/[C:17](=[N:19]/[O:20][CH:24]=[O:25])/[NH2:18])(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCOCC1
Reactant: N/C(=N\O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: O=CO
Product: N/C(=N\OC=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from (Z)-(2S)-1-[cyclohexylmethylsulfonyl]-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 28], formic acid, N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford (Z)-(2S)-1-[(cyclohexylmethyl)sulfonyl]-N′2-(formyloxy)-2-piperidinecarboximidamide as a colourless oil.
Reaction SMILES: [CH:1]1[C:6]([N:7]=[C:8]=[S:9])=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].[NH2:29][C:30]1[C:39]2[N:40]=[C:41]([CH2:46][CH2:47][CH2:48][CH3:49])[N:42]([CH2:43][CH2:44][NH2:45])[C:38]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]=1.O>N1C=CC=CC=1>[NH2:29][C:30]1[C:39]2[N:40]=[C:41]([CH2:46][CH2:47][CH2:48][CH3:49])[N:42]([CH2:43][CH2:44][NH:45][C:8]([NH:7][C:6]3[CH:1]=[CH:2][C:3]([C:13]4[C:14]5[C:15]([O:21][C:22]6[C:23]=4[CH:24]=[CH:25][C:26](=[O:28])[CH:27]=6)=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=5)=[C:4]([CH:5]=3)[C:10]([OH:12])=[O:11])=[S:9])[C:38]=2[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:31]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNC(=S)Nc1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Yield: 56.5 %

Procedure:
A solution of fluorescein-5-isothiocyanate (778 mg, 2.0 mmol) in pyridine (5 mL) was added to a solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine (566 mg, 2.0 mmol) in pyridine (5 mL). The reaction mixture was heated at reflux for 30 minutes and then poured into water (50 mL). The resulting orange solid was isolated by filtration, dried under high vacuum and then recrystallized from pyridine to provide 0.76 g of the desired product as an orange solid, m.p. >245°. Analysis by high performance liquid chromatography indicated pure product. Analysis: Calculated for C37H32N6O5S: % C, 66.06; % H, 4.79; % N, 12.49; Found: % C, 63.03; % H, 4.89; % N, 12.59. High resolution mass spectroscopy: TM=673.2233 Da., MM=673.2251 Da.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.Cl[CH:20]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@H:30]2[O:34][N:33]=[C:32]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:31]2)=[O:29])=[CH:23][CH:22]=1>CN(C=O)C>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([C:32]2[CH2:31][C@@H:30]([C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([CH:20]([N:10]([C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])[C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:22][CH:23]=3)=[O:29])[O:34][N:33]=2)[CH:36]=1
Reactant: O=C(Nc1ccc(C(Cl)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(c1ccccc1)c1ccc(NC(=O)[C@@H]2CC(c3cccnc3)=NO2)cc1
Temperature: 25 °C

Procedure:
) NaH (0.047 mol) was added portionwise to a solution of bis(1,1-dimethylethyl) imidodicarbonate (0.023 mol) in DMF (250 ml), stirred at RT (H2 gas evolution). The mixture was stirred for 30 minutes at RT. (5S)-N-[4-(chlorophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide monohydrochloride (0.0233 mol) was added portionwise and the resulting reaction mixture was stirred vigorously for 1 hour at RT (H2 gas evolution). The solvent was evaporated under reduced pressure. The residue was partitioned between water and CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure, yielding 1,1-dimethylethyl (5S)-[[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]phenylmethyl][(1,1-dimethylethoxy)carbonyl]carbamate (compound 501).
Reaction SMILES: C(OC[O:10][C@@H:11]1[C@@:27]2([CH3:28])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[CH:29]([CH3:45])[CH2:30][CH:31]=[C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:22]2[C@@H:13]([C@:14]3([CH3:62])[C@H:19]([CH2:20][C@H:21]2[O:46][Si](C(C)(C)C)(C)C)[CH2:18][C@H:17]([O:54][Si](C(C)(C)C)(C)C)[CH2:16][CH2:15]3)[CH2:12]1)C1C=CC=CC=1>CCOCC.C(S)C.[Cl-].[Zn+2].[Cl-]>[OH:54][C@@H:17]1[CH2:16][CH2:15][C@@:14]2([CH3:62])[C@H:19]([CH2:20][C@@H:21]([OH:46])[C@@H:22]3[C@@H:13]2[CH2:12][C@H:11]([OH:10])[C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C@@H:26]2[CH:29]([CH3:45])[CH2:30][CH:31]=[C:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:18]1
Reactant: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](OCOCc3ccccc3)[C@]12C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCS
Solvent: CCOCC
Product: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 12α-benzyloxymethoxy-3α,7α-di-tert-butyldimethylsilyloxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (4.63 g), 1M zinc chloride in ether (10.5 ml) and ethanethiol (2.0 ml) in ether (10 ml) is stirred at room temperature for about 30 minutes. The mixture is concentrated in vacuo and the residue taken up in ether. The ether solution is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:34])[C@@H:10]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1COCC1>[Si:1]([O:8][C@H:9]([CH3:34])[C@@H:10]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[C:11]1[S:44][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][N:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)s2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.8 %

Procedure:
To a 25-mL round bottom flask charged with a solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-benzohydrazide (326 mg, 0.65 mmol) in dry THF (10 mL) and equipped with a magnetic stirbar and septum was added Lawesson's reagent (527 mg, 1.3 mmol) under an atmosphere of nitrogen. This was stirred at room temperature for a period of 20 h. The solvent was then blown off under a gentle stream of nitrogen and the residue was directly purified via silica gel chromatography eluted with 30% EtOAc/hexanes to yield the product as a white solid (246 mg, 76%). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.90 (m, 2H), 7.46 (m, 3H), 7.31 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 5.19 (d, J=7.9 Hz, 1H), 5.00 (dd, J=3.1, 7.9 Hz, 1H), 4.50 (m, 1H), 2.27 (s, 3H), 1.21 (d, J=6.3 Hz, 3H), 1.02 (s, 9H), 0.24 (s, 3H), 0.17 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH:25]=[C:24]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([OH:20])[C:9]2[N:10]=[CH:11][N:12](S(N(C)C)(=O)=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.N>Cl.O.CO>[OH2:15].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:20])([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH:25]=[C:24]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)n1cnc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Cn1c(=O)cc(-c2ccccc2)c2cc(C(O)(c3ccc(Cl)cc3)c3c[nH]cn3)ccc21
Temperature: 110 °C
Yield: 49.7 %

Procedure:
A mixture of (±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.4 g) in hydrochloric acid (10 ml), water (30 ml) and methanol (15 ml) was stirred and heated at 110° C. for 14 hours. The mixture was cooled, basified with NH3 (aq.) and extracted with DCM. The organic layer was dried, filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2). The pure fractions were collected and evaporated. The residue (1.25 g) was crystallized from 2-propanone/DIPE, yielding 1 g (48.3%) of (±)-6-[(4-chlorophenyl)hydroxy(1H-imidazol-4-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone monohydrate (comp. 43).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:25](Cl)=[O:26])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[CH3:1][O:2][C:3]([CH2:4][NH:5][C:25]([C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:26])=[O:6]
Reactant: COC(=O)CN
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COC(=O)CNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from glycine-methyl ester and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][CH:5]=[C:6]([CH3:9])[C:7]=1Cl.[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[C:7]1[C:6]([CH3:9])=[CH:5][N:4]=[C:3]([CH2:10][OH:11])[C:2]=1[Cl:1]
Reactant: CNC
Reactant: Cc1cnc(CO)c(Cl)c1Cl
Solvent: CCO
Product: Cc1cnc(CO)c(Cl)c1N(C)C
Temperature: 2000 °C

Procedure:
3,4 -dichloro-5 -methyl-2 -hydroxymethylpyridine (4 g) was dissolved in 33 % dimethylamine in ethanol (11 ml), placed in a sealed vessel and heated to 2000° C. for 4 hours. On cooling, the reaction mixture was evaporated under reduced presure and the residue dissolved in water (15 ml) and ether extracted. Etherial extracts were dried (K2CO3 ), filtered and stripped to yield 4 -dimethylamino-3 -chloro-5 -methyl-2 -hydroxymethylpyridine, 4.08 g as an oil.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:12]=[CH:13][C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: COc1ccc(Oc2ccccc2Cl)cc1CC#N
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1cc(Oc2ccccc2Cl)ccc1OC
Yield: 96 %

Procedure:
A mixture of sodium ethoxide prepared from sodium metal (415 mg) and ethanol (20 ml), 2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetonitrile (4.7 g) and diethyl carbonate (7.8 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetate (5.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: O=C(O)CCCc1cccc(Cl)c1
Solvent: O=S(Cl)Cl
Product: O=C1CCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 35.72 of the product from Step B and 50 ml of thionyl chloride was heated at reflux for 2 hours and then stirred at room temperature for 18 hours. After this time thionyl chloride was removed at reduced pressure and the product was dissolved in carbon tetrachloride and concentrated at reduced pressure. The residue was dissolved in 150 ml of dichloroethane cooled to 0° C. and 28 g of aluminum chloride was added portionwise over about 1 hr in approximately 3 g portions. After stirring for 3 hrs the reaction was poured over a mixture of ice/1N HCl and extracted three times with methylene chloride. The organic extracts were dried over magnesium sulfate and concentrated to approximately 30 g of a brown oil. Chromatography on silica gel with 10% ethyl acetate/hexane afforded 17.83 g of 6-chloro-3,4-dihydro-1(2H)-naphthalenone as a brown oil. 1H NMR was consistent with the structure.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:43])[C@@H:10]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[C:34]=1[CH3:42])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC(OC)=CC=3)=[CH:18][CH:17]=2)=[N:14][N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH3:43])[C@@H:10]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[C:34]=1[CH3:42])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][N:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc(-c3nnc([C@H](Nc4ccc(C#N)c(Cl)c4C)[C@H](C)O[Si](C)(C)C(C)(C)C)o3)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.8 %

Procedure:
A 250 mL round bottomed flask was charged with 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(4-methoxybenzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (1.76 g, 2.84 mmol), methylene chloride —H2O (20:1, 80 mL) and 2,3-Dichloro-5,6-Dicyanobenzoquinone (3.87 g, 17.05 mmol). The reaction mixture was stirred at room temperature for 36 h and a saturated aqueous solution of sodium hydrogen carbonate (30 mL) was added followed by methylene chloride (70 mL). The phases were partitioned and the aqueous phase extracted with methylene chloride (60 mL) (×3). The combined organic extracts were dried (Na2SO4) and concentrated to furnish a white solid (1.33 g, 91%). 1H NMR (500 MHz, acetone d6, δ in ppm) δ 9.17 (br s, 1H), 7.85 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 6.99 (d, J=9 Hz, 2H), 6.84 (d, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 5.52 (d, J=9 Hz), 5.18 (dd, J=2 and 9 Hz, 1H), 4.74-4.68 (m, 1H), 2.41 (s, 3H), 1.46 (d, J=6 Hz, 3H), 0.86 (s, 9H), 0.1 (s, 3H) and −0.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:10]=2)[CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH2:25][N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:10]=2)[CH:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Nc2cccc(Cn3c(CN4CCOCC4)nc4ccccc43)c2)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Nc2cccc(Cn3c(CN4CCOCC4)nc4ccccc43)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
330 mg (6-Chloro-pyrimidin-4-yl)-[3-(2-morpholin-4-ylmethyl-benzoimidazol-1-ylmethyl)-phenyl]-amine (prepared in Example 92) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 424 mg anhydrous Na2CO3 (4 mmol) and 6 ml water were added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (132 mg, 37% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])C)=O)C1C=CC=CC=1.[ClH:20]>[Pd].CO>[ClH:20].[CH3:9][NH:11][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)CCNC

Procedure:
A mixture of ethyl 3-(N-benzyloxycarbonyl-N-methylamino)propionate (8 g), 10% palladium on carbon (1.6 g, 50% wet), conc.-hydrochloric acid (5.1 ml) in methanol (160 ml) was stirred for 5 hours at room+temperature under hydrogen atmosphere. Catalyst was removed by filtration and mother liquor was concentrated in reduced pressure to give ethyl 3-(methylamino)propionate hydrochloride (4.31 g).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]([C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH:30]([CH3:37])[CH2:31][O:32]3)=[CH:24][CH:25]=1)=[O:18])([CH3:16])[NH2:15]>ClCCl>[CH3:16][C:14]1([CH3:13])[NH:15][C:2](=[O:4])[N:19]([C:20]2[CH:21]=[N:22][C:23]([O:26][C:27]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:28]=3[CH2:29][CH:30]([CH3:37])[CH2:31][O:32]4)=[CH:24][CH:25]=2)[C:17]1=[O:18]
Reactant: CC1COc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c2C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1COc2cccc(Oc3ccc(N4C(=O)NC(C)(C)C4=O)cn3)c2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 123.1 %

Procedure:
In a 50 ml round-bottomed flask 2-methyl-N1-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}alaninamide (Intermediate 121, 72.6 mg) was dissolved in dichloromethane (5 ml) to give a pale yellow solution. TEA (0.142 ml, 1.021 mmol) was added and the reaction mixture was cooled at 0° C. A solution of triphosgene (27.3 mg, 0.092 mmol) in 1 ml of dichloromethane was added to the reaction mixture which was stirred at 0° C. After 15 minutes, additional solution of triphosgene (27.3 mg, 0.092 mmol) in 1 ml of dichloromethane was added to the reaction mixture. After 15 minutes, the reaction mixture was evaporated under vacuum to give the crude product which was purified via Biotage SP1 (using Cyclohexane/EtOAc as eluents from 3:1 to 1:2 in 10 CV; then 1:2 for 5 CV; 10 g SNAP Silica column). The collected fractions afforded the title compound 5,5-dimethyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione as a colourless oil (41.6 mg).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([NH:6][C:3]3[NH:4][CH:5]=[N:1][N:2]=3)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: Nc1nc[nH]n1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 1H-1,2,4-triazol-3-amine (66.6 g) and 1,4-dioxaspiro[4.5]decan-8-one (175 g) in acetic acid (1.25 L) was gradually added sodium triacetoxyborohydride (252 g) under ice-cooling. After stirring at room temperature for 16 hr, water (1 L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate (1 L). The mixture was neutralized with sodium bicarbonate, and extracted 3 times with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1, 2 L). The combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified with diisopropyl ether (500 mL), and the resulting solid was collected by filtration, washed twice with diisopropyl ether (250 mL), and dried to give the title compound (166 g, 94%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16](CO)[N:17]=1)[CH2:10][CH2:11][CH3:12].C(O)C>O1CCOCC1>[CH2:9]([C:13]1[NH:14][C:15]([CH2:20][OH:21])=[C:16]([Br:1])[N:17]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1nc(CO)c(CO)[nH]1
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCc1nc(Br)c(CO)[nH]1

Procedure:
3.56 Grams (20 mmol) of the N-bromosuccinimide was added to a solution consisting of 3.68 g (20.0 mmol) of the 2-butyl-4,5-bis(hydroxymethyl) imidazole, 40 ml of ethanol and 15 ml of dioxane maintained at a temperature of 45° to 50° C. with stirring. The mixture was further reacted at the same temperature for 30 minutes with stirring, and then the solvent was distilled off under reduced pressure. The obtained reaction product was washed with water and was recrystallized from acetonitrile to obtain a pale yellowish scale-like crystalline 2-butyl-4-bromo-5-(hydroxymethyl) imidazole in an amount of 2.36 g (yield, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18]([OH:31])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:21]2[CH:20]=[CH:19][C:18]([OH:31])=[CH:17][C:16]=2[CH3:15])=[N:8][C:7]=1[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C(C)C
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(-c2ccc(O)cc2C)nc1C(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of 2-bromo-4-isopropyl-thiazole-5-carboxylic acid ethyl ester (834 mg, 3 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.4 g, 6 mmol) and K2CO3 (828 mg, 6 mmol) in 1,4-dioxane/H2O (30 mL/5 mL) is bubbled nitrogen gas for 10 minutes. To this solution is added tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol). The reaction mixture is stirred at 100° C. overnight. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and 1N HCl. The organic phase is concentrated and purified by column chromatography (gradient: 0 to 15% EtOAc in hexanes) to give the title product (730 mg, 80%). 1H NMR (DMSO-d6) δ 9.99 (s, 1H), 7.68 (d, 1H), 6.68, 6.72 (m, 2H), 4.26 (q, 2H), 3.88 (m, 1H), 2.50 (s, 3H), 1.26 (t, 3H), 1.23 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19]Cl)([O:17]Cl)=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[O:4].[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>CCOCC>[F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19][NH:27][CH2:23][CH2:24][CH2:25][CH3:26])([O:17][NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[O:4]
Reactant: CCCCN
Reactant: COCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCCCNOP(=O)(CN(CC(=O)OCCOC)C(=O)C(F)(F)F)ONCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 2-methoxyethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (7.45 g, 0.0207 mole) in 125 ml. of ether was added dropwise with good stirring butylamine (6.05 g, 0.083 mole) in 40 ml. of ether. The reaction was stirred at room temperature overnight, then the reaction mixture was filtered, and the filtrate concentrated in vacuo. The residue was dissolved in fresh ether, washed with water, dried over MgSO4, and concentrated in vacuo to yield 2-methoxyethyl N-trifluoroacetyl-N-(bis(butylamino)phosphonomethyl)glycinate (4.0 g), ND =1.4572.