Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:7][CH2:8][CH2:9][NH:10][C:11]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:12]
Reactant: O=C1CCCN1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCCN1C(=O)NCCCl
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 65.1 g (765 mmol) of 2-oxopyrrolidine and 67.3 g (638 mmol) of chloroethyl isocyanate was heated with stirring at 95°-105° C. overnight. After cooling, the reaction solution was refined by silica gel chromatography. The resulting compound obtained from the eluate with toluene-ethyl acetate (20/1-10/1 v/v) was recrystallized from CH2Cl2 -ether-n-hexane, whereby 107.7 g of the objective compound 1-(2-chloroethylcarbamoyl)-2-oxopyrrolidine (III-1) melting at 66.5°-67.5° C. was obtained as crystals.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].O=C(CC(O)=O)CC(O)=O.[U:24]>>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[U+6:24].[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4]
Reactant: [U]
Agent: O=C(O)CC(=O)CC(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [U+6]

Procedure:
A 5.0 mM 1:1 uranium:citrate complex was prepared by combining equimolar amounts of citric acid and uranyl nitrate in deionized water. The pH of the sample was adjusted to 6.0 with 1N NAOH and the ionic strength to 0.1M with KCl. One hundred milliliters of the sample was transferred to 125 ml acid washed serum bottles and was incubated under 60 watt high output growth lights (Westinghouse, cool white #F24T12) at 25° C. Aerobic sample bottles were fitted with cotton plugs whereas the anaerobic samples were purged with nitrogen for about 20 minutes and then fitted with butyl rubber stoppers. Control samples were incubated in the dark. At periodic intervals samples were withdrawn and analyzed for pH, uranium and citric acid and its degradation products. Citric acid degradation products were identified by GC/MS. Under aerobic and anaerobic conditions, U(VI) citrate (aqueous) was photodegraded to yield a precipitate of U(VI) and citrate degradation products of acetic acid and CP2. Minor amounts of intermediate degradation products of citrate such as 3-oxoglutaric acid and a few unidentified products were also observed. Photodegradation of 1:1 uranium citrate complex under aerobic and anaerobic conditions is shown in FIG. 5. Photodegradation of uranium citrate complex was much more rapid and complete under aerobic conditions than under anaerobic conditions. Photodegradation of 1:1 uranium citrate complex showing the fate of uranium under aerobic conditions is presented in FIG. 6.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:25][CH:26]([CH:32]1[CH2:34][CH2:33]1)[C:27]([CH3:31])([CH3:30])[C:28]#[N:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:28]([C:27]([CH3:31])([CH3:30])[CH:26]([NH:25][C:13]([C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:5]=2)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[CH:11]=1)=[O:14])[CH:32]1[CH2:34][CH2:33]1)#[N:29]
Reactant: CC(C)(C#N)C(N)C1CC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C#N)C(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
In a flask were combined 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.36 mmol), 3-amino-3-cyclopropyl-2,2-dimethyl-propionitrile hydrochloride (75 mg, 0.43 mmol), HOBt (54 mg, 0.40 mmol), and EDC (77 mg, 0.40 mmol). Then added DMF (2 mL) followed by diisopropylethylamine (0.16 mL, 0.90 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (30% to 50% EtOAc/hexanes) to afford 121 mg (74%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2,2-dimethyl-ethyl)-amide as an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH3:18])[C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=[O:22])C1.OP([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:18]=[O:22])[C:12]3[O:16][CH:15]=[CH:14][C:13]=3[CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(C)c3occc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(C=O)c3occc3c2)cc1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a solution of 5-(4-methoxyphenyl)-7-methyl-benzofuran (1.60 g, 2.83 g 1:1 ratio with 4-methoxy-biphenyl 6.72 mmol) in carbon tetrachloride (190 ml) was added NBS (1.32 g, 7.40 mmol) and AIBN (50 mg). The solution was brought to reflux for 2 h, cooled to room temperature, and the solids were filtered off. The solution was then concentrated and anhydrous CH3CN (80 ml) was added. Then potassium benzeneselenite (2.14 g, 9.41 mmol), and K2HPO4 (1.17 g, 6.72 mmol) were added and then reaction was heated to reflux for 1 h after which it was allowed to cool to room temperature. The solution was then passed through a silica plug and concentrated under high vacuum. Chromatography (100% CH2Cl2) afforded 850 mg (50%) product as a white solid: mp 94–95° C.; 1H NMR (300 MHz, DMSO-d6): δ 3.82 (3H, s), 7.08 (2H, d, J=8.8 Hz), 7.14 (1H, d, J=2.2 Hz), 7.71 (2H, d, J=8.8 Hz), 8.10 (1H, d, J=1.9 Hz), 8.21 (1H, d, J=2.2 Hz), 8.25 (1H, d, J=1.9 Hz), 10.37 (1H, s); MS (ESI) m/z 253 ([M+H]+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.Cl.[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cccnc1

Procedure:
Following General Procedure C and using 3-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=150-152° C.). The reaction was monitored by tlc (Rf=0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:44])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:31](=[O:43])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)[NH:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:20][CH:19]=1)(C)(C)C.Cl>CO>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:44])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:31](=[O:43])[NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:37][CH:38]=2)[NH:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[CH:20][CH:19]=1
Reactant: CN(C)CCNC(C(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: CN(C)CCNC(C(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(/C=C/C(=O)Nc2ccccc2N)cc1
Yield: 24 %

Procedure:
(E)-[2-(3-{4-[(4-tert-Butyl-phenylcarbamoyl)-(2-dimethylamino-ethylamino)-methyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (crude material from Example 8) was treated with 1.25M HCl in methanol (2 mL) at room temperature for 2 hours. The reaction was quenched slowly with solid sodium bicarbonate until the pH was 6-7. The mixture was diluted in acetonitrile with a small amount of dimethylsulfoxide, passed through a 40 μm pipette filter, and then purified by preparative HPLC to obtain 16 mg desired product (24% over two steps). MS: calc'd 514 (MH+) exp 514 (MH+). 1H NMR (CD3OD, 400 MHz) δ 7.79 (d, 1H, J=15.6 Hz), 7.74 (d, 2H, J=8.2 Hz), 7.68 (d, 2H, J=8.2 Hz), 7.49 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=8.2 Hz), 7.36 (m, 4H), 6.93 (d, 1H, J=15.6 Hz), 3.40 (t, 2H, J=6.2 Hz), 3.23 (t, 2H, J=6.2 Hz), 2.95 (s, 6H), 1.31 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:16])[CH2:14][NH2:15])[CH2:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:26]([O:30][C:31]([NH:33][C:34]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:35]=1[C:36](O)=[O:37])=[O:32])([CH3:29])([CH3:28])[CH3:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>ClCCl>[C:26]([O:30][C:31]([NH:33][C:34]1[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][C:35]=1[C:36]([NH:15][CH2:14][C:13]([NH:12][C@@H:9]1[CH2:10][CH2:11][N:7]([CH2:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8]1)=[O:16])=[O:37])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (5.0 g, 18.7 mmol) in dichloromethane (100 mL) was treated with Et3N (2.9 mL, 20.5 mmol), 2-(tert-butoxycarbonylamino)-5-(trifluoromethyl)benzoic acid (6.27 g, 20.5 mmol), EDCI (3.9 g, 20.5 mmol) and HOBt (2.8 g, 20.5 mmol). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added 2 N aqueous NaOH solution (80 mL) and the mixture was extracted with dichloromethane. The extract was dried over anhydrous Na2SO4, filtered, and evaporated. Column chromatography (SiO2, hexane/ethyl acetate=1/1-1/4) afforded (R)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4-chlorobenzyl)pyrrolidine (9.41 g, 91%) as a white amorphous solid: ESI/MS m/e 555.2 (M+H, C26H+ClF3N4O4).
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Reactant: CC(=O)OC(C)=O
Product: CCC1(c2c[nH]c3c(NC(C)=O)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine and acetic anhydride, the title compound is prepared as in example 15. 0.16 g (46%). LC-MS m/z 337.1 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][C@@H:30]2[CH2:32][C@H:27]1[CH2:28][NH:29]2)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(CC)CC>CC#N>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH:30]2[CH2:32][CH:27]1[CH2:28][N:29]2[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: ClCc1ccc(Cc2nc3ccccc3s2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC1CN2Cc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
To a solution of 2-(4-chloromethyl-benzyl)-benzothiazole (1.0 g, 3.7 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.9 g, 4.4 mmol) in CH3CN (36 mL) was added Et3N (0.77 mL, 5.5 mmol) and the resulting solution was stirred at rt for 24 h. The reaction mixture was then concentrated and the crude residue was then partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (200 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 10% CH3OH in CH2Cl2) afforded the title compound as clear oil (0.88 g, 55%). MS (ESI): mass calcd. for C25H29N3O2S, 435.59; m/z found, 436.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 8.01 (d, J=8.2 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.37-7.34 (m, 5H), 4.44 (s, 2H), 4.40 (br s, 0.5H), 4.25 (br s, 0.5H), 3.75-3.75 (m, 2H), 3.64-3.44 (m, 2H), 3.17 (t, J=11.3 Hz, 1H), 2.90 (dd, J=25.2, 9.5 Hz, 1H), 2.74 (d, J=9.6 Hz, 0.5H), 2.55 (d, J=9.4 Hz, 0.5H), 1.88-1.86 (br m, 1H), 1.73-1.65 (br m, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[S:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH:16]=[CH2:17])=[CH:10][C:9]=1[N+:18]([O-])=O)=[O:4].CO>[Fe].O>[CH3:1][O:2][C:3]([NH:5][C:6](=[S:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH:16]=[CH2:17])=[CH:10][C:9]=1[NH2:18])=[O:4]
Reactant: C=CCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: C=CCSc1ccc(NC(=S)NC(=O)OC)c(N)c1

Procedure:
1.5 G. of 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-(prop-2-en-1-ylthio)benzene is treated for four hours in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform and washed with water, and then the solvent is evaporated affording 1-(3-methoxycarbonyl-2-thioureido)-2-amino-4-(prop-2-en-1-yl-thio)benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.076 mol of the compound obtained in Step C is introduced in a 500 ml round-bottomed flask, and then 250 ml of water and 0.152 mol of NaOH are added. The reaction mixture is stirred for 12 hours at ambient temperature. The reaction mixture is then acidified with 3M HCl and is extracted twice with ethyl ether. The organic phase is dried over MgSO4 and evaporated under reduced pressure to obtain the title product in the form of a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][N:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:26]=1>>[CH3:20][O:19][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 438.09 g/mol.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].II.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].[Cl-].[NH4+]>CCOCC>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]([OH:21])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: COc1cccc(C=O)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(C(O)c2cccc(C(F)(F)F)c2)c1

Procedure:
m-Trifluoromethylbromobenzene (48 g.) in dry ether (160 ml.) is added dropwise and with stirring to magnesium turnings (5.2 g.) just covered with dry ether. After the addition of the first 10 ml. of solution, reaction is initiated by introduction of a crystal of iodine and the addition is then continued at such a rate as to maintain gentle refluxing. When all the m-trifluoromethylbromobenzene has been added and the reaction has subsided, m-methoxybenzaldehyde (27.2 g.) in dry ether (160 ml.) is added dropwise to the stirred Grignard reagent at such a rate as to maintain gentle refluxing. When all the m-methoxybenzaldehyde has been added, the reaction mixture is heated under reflux for 2 hours and then allowed to cool. Excess saturated aqueous ammonium chloride is added, the ethereal layer is separated, washed with water and with brine, dried (MgSO4) and the ether evaporated to give an oil which crystallises and is recrystallised from petroleum ether (b.p. 40°-60°C.) to give 3-methoxy-3'-trifluoromethylbenzhydrol, m.p. 51°-52°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([O:24]C)=[O:23])=[CH:21][C:16]=2[C:15](=[O:26])[N:14]([C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH3:28])[C@@H:13]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:12]1=[O:43])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([O:5][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=2[C:15](=[O:26])[N:14]([C@@H:27]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH3:28])[C@@H:13]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[C:12]1=[O:43])=[O:44])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2CCCCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(C(=O)O)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)[C@@H]1c1ccc(Cl)cc1
Yield: 77.4 %

Procedure:
A solution of 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-methoxycarbonyl-2,5-dioxo-3,4-dihydro-1H-1,4-benzodiazepin-1-yl]valeric acid tert-butyl ester (Example 32) (200 mg, 0.31 mmol) and NaOH (1N in water, 380 μL) in THF/MeOH/H2O (2 mL/400 μL/100 μL) was stirred at room temperature for 12 h. The mixture was evaporated to dryness. Then, the residue was dissolved in water (10 mL) and the pH was adjusted to 4 with 1N HCl. The solution was extracted with ether (3×20 mL), then the organic layer was dried (Na2SO4) and concentrated to dryness under reduced pressure. Filtration over silica gel afforded the title compound (150 mg, 77%): Mass spectrum (LCMS, ESI pos.): Calcd for C33H34Cl2IN2O6: 624.18; found 568.9 (M+H—t-bu).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]#[N:22].C>CC(C)=O.CCCCCC.C(OCC)(=O)C>[C:21]([CH2:20][O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=1[NH2:1])#[N:22]
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(OCC#N)c(N)c1

Procedure:
2-Amino-4-(1,1dimethylethyl)phenol (90.0 g, 546 mol, described in Example 1) was dissolved in acetone (900 ml) and heated at reflux for 2 days in the presence of anhydrous potassium carbonate (81.0 g, 534 mmol) and chloroacetonitrile (40.5 g, 535 mmol). The mixture was allowed to stand for an additional day at 20°-24° C. The mixture then was treated with more potassium carbonate (15.0 g) and chloroacetonitrile (10 g) under the same conditions. The mixture was mixed with charcoal and filtered through diatomaceous earth. The filtrate was evaporated to afford a residue which, when dissolved in hexane containing a small amount of ethyl acetate, afforded tan crystals of the title compound; Anal. Calc'd for C12H16N2O: C, 70.56%; H, 7.90%; N, 13.72%; Found: C, 70.60% H, 8.00%; N, 13.85%; IR(CHCl3) 3460, 3380, 2240, 1620, 1515, 1166, cm-1 ; NMR(CDCl3) δ 1.3 (s, 9H), 3.7 (s,2H), 4.7 (s,2H), 6.75 (s, 3H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([I:35])C(=O)C1>CC(C)=O>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([I:35])=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCCC3)cnc21
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCn1cc(I)c2nc(NC(=O)NC3CCCCC3)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
The mixture of 1-Cyclohexyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (2.67 g) and NIS (742 mg, 3.30 mmol) in 12 mL of acetone was stirred at RT for 4 hr, filtered, and washed with small amount of acetone. The solid was dried under high vacuum to give 701 mg of 1-cyclohexyl-3-[7-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as an off-white solid (45% yield for 2 steps).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[C@H:15]12[CH2:21][C@H:18]([NH:19][CH2:20]1)[CH2:17][N:16]2C(OC(C)(C)C)=O>>[C@H:15]12[CH2:21][C@H:18]([NH:19][CH2:20]1)[CH2:17][N:16]2[CH2:14][C@@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[OH:13]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Product: Cc1c([C@@H](O)CN2C[C@@H]3C[C@H]2CN3)ccc2c1COC2=O

Procedure:
5-{(1R)-2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1 (3H)-one was prepared in an analogous fashion as described for the synthesis of INTERMEDIATE 3 starting from 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one (INTERMEDIATE 2) and commercially available tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:14][N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C:26]3([N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][NH:24][C:25]3=[O:32])[CH2:31][CH2:30]2)[C:6]1=[O:15]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCN2CCC3(CC2)C(=O)NCN3c2ccccc2)c2ccccc21
Temperature: 70 °C

Procedure:
A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.4 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 2.65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide is stirred and heated for 2 hours at 70° C. The reaction mixture is cooled and poured onto water, whereupon an oily precipitate is formed. The supernatant aqueous phase is decanted and the residual oil is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1 part of 8-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]-decan-4-one; mp. 164.4° C.