Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37]C1(C2C=CC=CC=2)CCCCN1.C(OC1C=CC=CC=1CN(CC1C=CC=CN=1)CCCCl)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6]1[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=1[CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[O:37][CH3:36])[CH2:17][CH2:18]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1(c2ccccc2)CCCCN1
Reactant: CC(C)(C)Oc1ccccc1CN(CCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Agent: CC(C)(C)Oc1ccccc1CN(CCCCl)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1C1CCN(CCCN(Cc2ccccn2)Cc2ccccc2OC(C)(C)C)CC1
Yield: 59 %

Procedure:
The same procedure as described for compound 20 was applied to 2-methoxy-2-phenylpiperidin (0.33 g, 1.73 mmol), compound 19 (0.4 g, 1.15 mmol), KI (0.57 g, 3.45 mmol) and K2CO3 (0.79 g, 5.75 mmol). Purification was carried out on a silica gel TLC plate that was developed in with a 5% methanolic NH3 (7 M NH3 in methanol/95% CH2Cl2. The product was isolated as pale yellow oil (59%). 1H NMR (CDCl3) δ 8.486 (m, 1H, Ar), 7.591 (m, 3H, Ar), 7.22 (dd, 1H, Ar), 7.135 (m, 3H, Ar), 7.017 (dd, 2H, Ar), 6.901 (dd, 1H, Ar), 6.819 (d, 1H, Ar), 3.781 (s, 3H, —OCH3), 3.764, (s, 2H, —CH2—), 3.691 (s, 2H, —CH2—), 3.002 (d, 2H, —CH2—), 2.939 (m, 1H, —CH—), 2.521 (t, 2H, —CH2—), 2.373 (t, 2H, —CH2—), 2.053 (m, 3H, —CH—CH2—), 1.769 (m, 6H), 1.354 (s, 9H, —C(CH3)3). Mass Spec.=502.34 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Si:20]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(O)cc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (30.1 g; manufactured by Wako Pure Chemical Industries, Ltd.) and imidazole (18.3 g; manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in dehydrated DMF (436 mL; manufactured by Kanto Chemical Co., Inc.). After cooling to 0° C., TBDMSCl (48.3 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred for 1 hour while warming to room temperature. Solvent contained in the reaction solution was evaporated under reduced pressure. After adding water, extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, purification was carried out with column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=100:0→94:6) to obtain the title compound (40.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=O)[CH3:24].[Na].C(=O)([O-])O.[Na+]>ClC(Cl)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[C:12]([NH:15][CH2:23][CH3:24])=[N:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2N)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCNc1ncc(Nc2ccc(Cl)cc2)nc1-n1nc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
5-(4-Chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl) -pyrazine-2-amine (84 mg, 1.5 mmol) was dissolved in dichloroethane (4 mL). Acetaldehyde (83 μL, 1.5 mmol) was added and the reaction mixture was stirred for one hour at room temperature. Sodium triaceoxyborohydride (70 mg, 0.3 mmol) was added and the reaction mixture was stirred overnight at room temperature. Aqueous sodium hydrogen carbonate and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/heptane as eluent) to give 5-(4-chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl)-2-ethylamino-pyrazine (49 mg, 80%) as a green solid. Mp. 122-124° C. LC-ESI-HRMS of [M+H]+ shows 343.1444 Da. Calc. 343.143797 Da, dev. 1.8 ppm
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1.[CH2:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: CCCCCCCCI
Reactant: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Product: CCCCCCCCOc1cc2cc(C(=O)OC)c(C(=O)OC)c(-c3ccncc3)c2cc1OC

Procedure:
1-(4-Pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene and octyl iodide are treated in the same manner as in Reference Example 117-(2) to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-octyloxy-7-methoxynaphthalene.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>CN(C=O)C>[CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[N:12]([S:30]([C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])[CH:11]=[CH:10]3
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1c2c(ccc3c2ccn3S(=O)(=O)c2cccs2)OCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-thiophenesulfonyl chloride (21 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 1-methyl-8-(2-thienylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (14 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (5 mg). MS m/z 349 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH2:4]([N:8]1[C:12]([C:13](OCC)=[O:14])=[C:11]([CH:18]=O)[N:10]=[C:9]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:5]#[C:6][CH3:7]>C(O)C>[CH2:4]([N:8]1[C:12]2[C:13](=[O:14])[N:2]([CH3:1])[N:3]=[CH:18][C:11]=2[N:10]=[C:9]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:22][CH2:21]1)[C:5]#[C:6][CH3:7]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OCC
Reactant: CNN
Solvent: CCO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Temperature: 80 °C
Reaction time: 15 h

Procedure:
0.05 ml of methylhydrazine was added to a 2.5-ml ethanol solution of 0.055 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate. The mixture was stirred at 80° C. for 15 hours, and then heated at 130° C. for 14 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography. Thus, 0.035 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([Si:42]([C:47]#[CH:48])([CH2:45][CH3:46])[CH2:43][CH3:44])[CH3:41]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:43]([Si:42]([C:40]#[C:41][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1)([CH2:47][CH3:48])[CH2:45][CH3:46])[CH3:44]
Reactant: C#C[Si](CC)(CC)CC
Reactant: CCOC(=O)Cc1cncnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cncnc1C#C[Si](CC)(CC)CC
Temperature: 120 °C
Yield: 94 %

Procedure:
To a nitrogen de-gassed solution of ethyl 2-(4-chloropyrimidin-5-yl)acetate (I108) (0.823 g, 4.10 mmol) in dry DMF (15 mL) were added triethylamine (1.715 mL, 12.31 mmol) followed by triphenylphosphine (0.124 g, 0.473 mmol), trans-dichlorobis(triphenyl-phosphine)palladium(II) (0.144 g, 0.205 mmol), Cu(I)I (0.078 g, 0.410 mmol) and finally (triethylsilyl)acetylene (1.470 mL, 8.204 mmol). The reaction mixture was then heated under microwave irradiation at 120° C. for 25 minutes, concentrated in vacuo and purified by silica gel chromatography (Isolera Biotage, 40 g Si cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I109) (1.176 g, 94% yield) as a yellow-orange oil; 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.68 (s, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.80 (s, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.10-1.01 (m, 9H), 0.77-0.67 (m, 6H) LCMS Method C: rt 6.64 min; m/z 305.1 [M+H]+.
Reaction SMILES: CC1C=CC2C(=C(O)C=CC=2)N=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([OH:36])[C:18]([CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=2)[N:15]=1>>[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[C:17]([OH:36])[C:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:19][CH:20]=2)[N:15]=1
Reactant: CCCCCCCCCCC=Cc1ccc2ccc(C)nc2c1O
Agent: Cc1ccc2cccc(O)c2n1
Product: CCCCCCCCCCCCc1ccc2ccc(C)nc2c1O

Procedure:
Example I was essentially repeated using 2-methyl-8-hydroxyquinoline in place of 5-chloro-8-hydroxyquinoline. The resultant 2-methyl-7-dodecenyl-8-hydroxyquinoline was hydrogenated by the procedure of Example II, Part B to give 2-methyl-7-dodecyl-8-hydroxyquinoline.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH2:60])[C:55]([CH3:61])=[CH:54]2>CN(C=O)C.O.CCOC(C)=O>[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH:60][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[C:55]([CH3:61])=[CH:54]2
Reactant: Cc1cc2cc(F)ccc2n1N
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1c(C)cc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (810 mg, 3.76 mmol), PyBrOP (1.76 g, 3.78 mmol), and DIPEA (1.9 mL, 10.89 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-2-methyl-indol-1-ylamine (560 mg, 3.41 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 3% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)-amide (174 mg, 14%) as a solid. MS: 362 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 11.82 (s, 1H), 9.30 (d, 1H), 8.81 (d, 1H), 8.46 (d, 1H), 8.03 (dt, 1H), 7.59 (dd, 1H), 7.43 (dd, 1H), 7.29 (dd, 1H), 6.98 (dt, 1H), 6.35 (s, 1H), 2.79 (s, 3H), 2.38 (s, 3H). IC50=8 nM.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[CH3:23][NH:24][CH:25]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:26]1
Reactant: CNC1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CNC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and N-methylpyrrolidin-3-amine to give 260. MS: (ESI+)=396.1
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(CCO)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (5 g) in acetone (45 mL) was added anhydrous potassium carbonate (6.5 g) at room temperature, and the mixture was stirred for 30 minutes. Ethyl bromoacetate (4.4 mL) was added dropwise to the reaction mixture at 40-45° C. of internal temperature, and the mixture was stirred at 40° C. for 8 hours. After the insoluble materials were filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give ethyl 2-[4-(2-hydroxyethyl)phenoxy]acetate (5.8 g).
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].[N:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[C:10]=[O:11].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:9][C:10]([NH:2][CH:3]2[CH2:8][CH2:7][O:6][C:4]2=[O:5])=[O:11])=[CH:14][CH:15]=1
Reactant: NC1CCOC1=O
Reactant: Cc1ccc(CN=C=O)cc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)NC2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.6 %

Procedure:
A 0° C. slurry of α-amino-γ-butyrolactone hydrobromide (25 g, 0.137 mol) in THF (200 mL) was combined with 1-isocyanatomethyl-4-methyl-benzene (20.6 g, 0.139 mol) and then treated dropwise with N,N-diisopropylethylamine (19.5 g, 0.151 mol). The reaction mixture was stirred for at room temperature for 2 h. The solvent was removed in vacuo to give 48.5 g crude 1-(4-methyl-benzyl)-3-(2-oxo-tetrahydro-furan-3-yl)-urea that was utilized directly in the next reaction without purification. MS (ES30 ) Calc'd for C13H17N2O3 (M+1) 249. Found m/z 249 (100%). 1H NMR.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][S:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:18][S:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:22][CH:21]=1
Reactant: c1nc2ccc(NCC3CCCCC3)cc2[nH]1
Reactant: CSc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1ccc(CN(CC2CCCCC2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-cyclohexylmethyl-benzimidazol-5-amine (115 mg; 0.5 mmol; 1 eq.), 4-methylthiobenzylbromide (120 mg; 0.55 mmol; 1.1 eq.) and K2CO3 (76 mg; 0.55 mmol; 1.1 eq.) according to method 6; Yield: 0.068 g (37.3%); MS m/z: 366.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.90-1.00 (m, 2H); 1.13-1.23 (m, 3H); 1.61-1.76 (m, 6H); 2.41 (s, 3H); 3.24 (d, 2H, 3J=6.6 Hz); 4.52 (s, 2H); 6.67-6.69 (m, 2H); 7.12-7.18 (m, 4H); 7.32-7.34 (m, 1H); 7.89 (s, 1H); 11.84 (br s, 1H); HPLC (METHOD [A]): rt 18.51 min (97.8%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[Br:17][CH2:18][C:19]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])=[O:20]
Reactant: O=C(Br)CBr
Reactant: COCCNCCOC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CCOC)C(=O)CBr
Temperature: -78 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a stirred solution of DCM, bis(2-methoxyethyl)amine (40.0 g, 44.0 mL, 300 mmol), and triethylamine (69.25 mL, 500 mmol), under a nitrogen atmosphere at −78° C. was added drop wise bromo acetyl bromide (34.8 mL, 400 mmol). After stirring at −78° C. for 5 h, the reaction mixture was allowed to warm up to −20° C. and then quenched by addition of water (60 mL). The organic phase was washed with distilled water (3×30 mL), saturated ammonium chloride (3×30 mL), saturated sodium bicarbonate (3×30 mL) and brine (2×30 mL). The organic phase was then dried over magnesium sulfate, filtered and solvents removed via rotary evaporation to yield a crude product in 82% yield (62.3 g, 245 mmol). The crude product was then distilled under high vacuum at 170° C. to give pale yellow crystals in 49% yield (35.57 g, 140 mmol). Pure product can also be recrystallised from the crude material with diethyl ether.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[C:15](O)=O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].O1CCCC1.C[Si]([Cl:30])(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13](=[O:20])[C:14](=[CH:18][CH:19]=2)[CH2:15][Cl:30])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Reactant: C[Si](C)(C)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc(-c2ccc(CCl)c(=O)[nH]2)c1

Procedure:
A stirred suspension of 2.6 g. of 6-[3-(aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 130 ml. of tetrahydrofuran is treated with 1.24 ml. of triethylamine. After a few minutes, the resulting solution is treated with 1.12 ml. of trimethylsilyl chloride and stirred 1 hour at room temperature. The solution is then treated with 1.28 ml. of thionyl chloride and stirred for 2 hours at room temperature. The resulting solution is diluted with 200 ml. of hexane and the precipitate of 6-[3-aminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride is collected by filtration, washed with hexane and dried. The acid chloride is used as such without further purification.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:15]=3[N:14]=2)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.C(=O)([O-])[O-:31].[K+].[K+]>CS(C)=O.O.OO.CCOC(C)=O>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[C:25]([C:28]([NH2:29])=[O:31])[CH:26]=[CH:27][C:15]=3[N:14]=2)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(C#N)cc2n1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(C(N)=O)cc2n1-c1ccccc1
Reaction time: 1 h
Yield: 168.5 %

Procedure:
To a solution of (S)-2-(1-(9H-purin-6-ylamino)ethyl)-1-phenyl-1H-benzo[d]imidazole-6-carbonitrile 122 (70 mg, 0.18 mmol) in DMSO (2 mL) was added potassium carbonate (10 mg, 0.07 mmol) followed by hydrogen peroxide (30%, 0.2 mL). After 1 h stirring, additional potassium carbonate (10 mg, 0.07 mmol) in water and hydrogen peroxide 90.2 mL) were added and stirring was continued for 1 h. The solution was then diluted with water (30 mL) and EtOAc was added. A precipitate formed and was filtered off affording 137 as a white solid (47 mg, 64%). LCMS: RT 2.41 min [M+H]+ 399.1. 1H NMR (DMSO, 400 MHz): δ 8.20-8.07 (2H, m), 8.03-7.92 (2H, m), 7.81 (1H, d, J=9.19 Hz), 7.76-7.50 (6H, m), 7.24 (1H, s), 5.51 (1H, bs), 1.58 (3H, d, J=6.84 Hz)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34].Cl.C([O-])(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](/[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:22][CH:23]=1
Reactant: COC(=O)CCCCCCCC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (500 mg), methyl 9-oxo-9-phenylnonanoate (464 mg), 1N hydrochloric acid (3 ml), sodium acetate (264 mg) and methanol (20 ml) was heated to reflux for 72 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain an oil from an ethyl acetate-hexane (1:6, v/v)-eluted fraction. This was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), a 1N aqueous saturated solution of sodium hydroxide (5 ml) was added and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-9-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-9-phenylnonanoic acid (323 mg, yield 37%) as colorless crystals. m.p. 67-68° C.