Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][Cl:7])[CH3:2].C(O)C[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(O)(=O)=O>[N+](C)([O-])=O>[Cl:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH2:2][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCc1ccccc1
Reactant: CCOC(CCCl)OCC
Agent: CS(=O)(=O)O
Solvent: C[N+](=O)[O-]
Product: CCOC(CCCl)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Chloropropionaldehyde diethyl acetal (LXII, 30.66 g, 0.184 mol) is added to an ice-cooled solution of phenethyl alcohol (XLV, 20.44 g, 0.167 mol) in nitromethane (50 ml) is added and methanesulfonic acid (1.61 g, 0.0167 mol). After 30 min the ice bath is removed and the mixture is allowed to stir overnight. The mixture is then warmed in a water bath at approximately 40-50° under reduced pressure for 10-20 min (no appreciable removal of nitromethane occurs but there is some further reaction observed). The mixture is partitioned between ethyl ether and saline, the layers are separated and the organic phase is dried over megnesium sulfate and concentrated under reduced pressure. The curde material is stored overnight in the refreigerator and then chromatographed on silica gel eluting with hexane and then ethyl acetate/hexane (2/98). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.20, 2.05, 2.87, 3.43-3.86, 4.69 and 7.24 δ.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10](C)C(=O)O[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]([NH:22][CH2:23][CH2:24][NH2:25])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15](=[O:16])[NH:22][CH2:23][CH2:24][NH:25][C:7](=[O:14])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:11]=1[NH2:10])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cn1c(=O)oc(=O)c2cccc(Cl)c21
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cccc(Cl)c1N
Yield: 84 %

Procedure:
Starting from 8-chloro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione and N-Boc-ethylenediamine and using Procedure S, the title intermediate was obtained as a colourless solid (264 mg; 84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:26](=[O:27])[CH2:25][C@@H:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]2[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]12
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCNC(=O)OC(C)(C)C)c1nnc(C)n1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCN)c1nnc(C)n1-2
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl [5-({[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetyl}amino)pentyl]carbamate (for a preparation see Reference compound I) (0.2 g, 0.34 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.053 ml, 0.68 mmol) dropwise at 0° C. The reaction mixture was stirred for 3 h from 0° C. to room temperature. The reaction mixture was concentrated to dryness to afford the title compound as a hygroscopic yellow oil (200 mg)
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:53]=[CH:52][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([O:30]CC3C=CC(OCC4N=C(C5C=CC=CC=5)OC=4C)=CC=3)=[O:29])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[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:53]=[CH:52][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COC(=O)Cc2cccc(OCc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccc(CC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a mixture of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl 2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (2.40 g), tetrahydrofuran (7 mL) and ethanol (7 mL) was added 1N aqueous sodium hydroxide solution (7.0 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and water and diethyl ether were added to the residue. Dilute hydrochloric acid was added to acidify the aqueous layer, and the precipitated solid was collected by filtration, and dried with air to give crystals (1.24 g, 85%) of 2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: [Cl:1][CH2:2][P:3](Cl)([CH2:5][Cl:6])=[O:4].O1CCCC1.[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(OCC)C>[Cl:1][CH2:2][P:3](=[O:4])([CH2:5][Cl:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=P(Cl)(CCl)CCl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=P(CCl)(CCl)c1ccccc1

Procedure:
A three-necked reaction vessel equipped with a reflux condenser, mechanically driven stirrer, nitrogen inlet and thermometer was charged with 91 g. of bis(chloromethyl)phosphinic chloride and 150 cc. tetrahydrofuran. A 280 g. portion of a tetrahydrofuran solution containing 2.0 moles of phenylmagnesium chloride per kilogram of solution was gradually added to the reaction mixture at a rate such that the temperature of the reaction mixture did not exceed 30° C. The resultant mixture was stirred for one hour following completion of the addition, at which time an excess of water was added and the organic phase isolated. The aqueous phase was extracted once with chloroform and the chloroform layer combined with the previously isolated organic layer. The organic solvents were then evaporated under reduced pressure to yield an offwhite solid which was slurried with a small amount of diethyl ether and filtered. The isolated solid material weighed 62.0 g. and melted from 135° to 137° C. The reported melting range for the compound is 141°-142° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C[O:9][C:10]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[CH:14]=[C:15]([C:33]#[N:34])[CH:16]=[CH:17][C:18]=1[N:19]2[CH:24]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:26]([CH2:27][CH2:28]2)[CH2:25]1.C(N(CC)C(C1C=CC2N(C3CC4N(CCC5C=CC=CC=5)C(CC4)C3)C3C(OC=2C=1)=C(OC)C=CC=3)=O)C>>[OH:9][C:10]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:11]=1[O:12][C:13]1[CH:14]=[C:15]([C:33]#[N:34])[CH:16]=[CH:17][C:18]=1[N:19]2[CH:24]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:26]([CH2:27][CH2:28]2)[CH2:25]1.[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COc1cccc2c1Oc1cc(C#N)ccc1N2C1CC2CCC(C1)N2C
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CC2CCC(C1)N2CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C2CCC1CC(N1c3ccc(C#N)cc3Oc3c(O)cccc31)C2

Procedure:
Using an adaptation of Procedure 13, substituting the TFA salt of 6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile, 3p for the TFA salt of 6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 6e, the title compound 6-hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile, 4p was obtained as TFA salt and as a mixture of endo and exo isomers after purification via reverse phase HPLC (eluent gradient: 20% to 45% CH3CN in water containing 0.1% TFA). MS m/z=348 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][Br:16]>>[BrH:16].[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:15][CH2:14][O:13][CH3:12])[C:7](=[NH:9])[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: COCCBr
Product: Br
Product: COCCn1c(=N)sc2cc(F)ccc21

Procedure:
Commercially available 6-fluoro-benzothiazol-2-ylamine and 2-bromoethyl methyl ether were processed as described for example 12A to afford the title compound. MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10])(=[O:31])=[O:32]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 2-methoxy-5-methylbenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 390 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-methylbenzenesulfonylamino)phenyl]-amide. LC: Tr 1.25 min; MS: 489.1 (M+1)+.
Reaction SMILES: Br[C:2]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])(C)(C)C.CN(C)[CH:26]=[O:27].Cl>O1CCCC1.C(OCC)C.O>[CH2:7]([O:6][CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:2]=1[CH:26]=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(CCOCc2ccccc2)c1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(CCOCc2ccccc2)c1C=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
To a solution of benzyl 2-bromo-3-methylphenethyl ether (3.2 g, 0.0105 mol) in dry tetrahydrofuran in a nitrogen atmosphere at −65° C. was added tert-butyllithium (1.7 M in pentane)(10.5 ml, 0.018 mol) and the mixture was stirred at −20° C. for 30 min. Dimethylformamide (1.5 g, 0.021 mol) was added dropwise at −65° C. and the mixture was stirred at −20° C. for 30 min and at room temperature for 1 h. To the solution was water added carefully and 2M HCl to make it acidic and the mixture was stirred for 30 min. To the mixture was added diethyl ether (50 ml), the organic layer was separated, washed with saturated sodium carbonate and water. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using heptane:methylene chloride (2:8) as eluent gave 1.0 g (38.5%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[C:13]=2[Br:19])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[S:31])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[C:13]=2[Br:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(Br)c2Br)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=S)Nc2cccc(Br)c2Br)cc1

Procedure:
The thioamide was prepared according to Example 19 using the 4-tert-butyl-N-(2,3-dibromophenyl)benzamide of Example 22, and Lawesson's reagent in toluene. MS (ESI) m/z 426; HPLC Method B, purity 96.3% at 210-370 nm, 11.4 min.; 98.3% at 262 nm, 11.4 min.; HRMS: calcd for C17H17Br2NS+H+, 425.95212; found (ESI, [M+H]+), 425.9527.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([N:29]2[C:34](=[O:35])[NH:33][C:32](=[O:36])[CH:31]=[N:30]2)=[CH:25][C:21]=1[C:22](Cl)=[O:23].CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>ClC(Cl)C.C1COCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([N:29]2[C:34](=[O:35])[NH:33][C:32](=[O:36])[CH:31]=[N:30]2)=[CH:25][C:21]=1[C:22]([NH:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:23]
Reactant: CCCCC(CC)CN
Reactant: O=C(Cl)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)CNC(=O)c1cc(-n2ncc(=O)[nH]c2=O)ccc1Cl
Reaction time: 16 h

Procedure:
To a solution of 2-ethylhexylamine (15 mg, 0.125 mmol) in dichloroethane (1 ml) was added diisopropylethylamine resin (60 mg, 0.225 mmol) followed by a solution of 2-chloro-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzoyl chloride (21 mg, 0.075 mmol) in a 3:1 mixture of dichloroethane and THF (15 ml). The reaction mixture was shaken for 16 hours and filtered. The filtrate was treated with MP-carbonate resin (75 mg, 0.225 mmol) and the resulting mixture was shaken for 3 hours. The mixture was filtered and the resin washed with dichloromethane followed by 9:1 methanol/acetic acid. The combined filtrates were concentrated under reduced pressure to give the title compound as an amorphous solid. Mass spec [M−1] 3:1 ratio of 377.2 and 379.2; 1H nmr (500 MHz, CDCl3) δ 0.92 (t, 3H), 0.96 (t, 3H), 1.26–1.66 (m, 9H), 3.46 (m, 2H), 6.26 (broad s, 1H), 7.51 (d, 1H), 7.59–7.62 (m, 2H), 7.94 (s, 1H), 8.72 (broad s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2c(Cl)cccc2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)cccc2c1Cl

Procedure:
The dichloride was prepared according to Procedure E using 2,4,8-trichloro-3-methylquinoline (0.475 g, 1.927 mmol), 2-(tributylstannyl)pyridine (0.780 mL, 2.120 mmol), palladium tetrakistriphenylphosphine (0.223 g, 0.193 mmol) in toluene (3.85 mL) to give 4,8-dichloro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=289.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:21]([CH:18]1[CH2:20][CH2:19]1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)OCc2ccccc2)C(NC(=O)C2CC2)=N1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (100.0 mg, 0.43 mmol), cyclopropanecarbonylchloride (45.0 mg, 0.43 mmol) and Hunig's base (83.0 mg, 0.64 mmol) in acetonitrile (4 mL) was heated to reflux under argon for 0.5 hr. Cooled to r.t., the reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated and the residue was triturated with AcOEt to give a suspension. The solid was filtered to give 2-(cyclopropanecarbonyl-amino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as an oil (113.0 mg, 87.6%).
Reaction SMILES: [ClH:1].Cl.C1[C:17]2[CH:16]=[CH:15][CH:6]([C:7](=O)[N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:5](=O)[C:4]1=2.[Cl:19][CH:20]([CH3:36])[C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:34][CH3:35])[C:29]=2[Cl:33])[CH:24]=1)=[O:22].[C:37]([O-])([O-:39])=[O:38].[K+].[K+]>CN(C=O)C>[ClH:19].[ClH:1].[CH2:37]1[O:39][C:17]2[CH:16]=[CH:15][C:6]([CH2:7][N:8]3[CH2:9][CH2:10][N:11]([CH:20]([C:21]([C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:34][CH3:35])[C:29]=5[Cl:33])[CH:24]=4)=[O:22])[CH3:36])[CH2:12][CH2:13]3)=[CH:5][C:4]=2[O:38]1
Reactant: COc1ccc2cc(C(=O)C(C)Cl)ccc2c1Cl
Reactant: O=C1C2=C(C=CC1C(=O)N1CCNCC1)C2
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccc5c(c4)OCO5)CC3)ccc2c1Cl
Yield: 25.5 %

Procedure:
A mixture of N-(3,4-methylenedioxobenzyl)piperazine dihydrochloride (1 g, 4.5 mmol), 2-chloro-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.54 g, 5.4 mmol) and K2CO3 (1.57 g, 11.25 mmol) in 20 ml of DMF, was treated according to general preparation 2 to give 0.62 g of compound (IV-30), yield 70%, mp 230-232° C. M+ 466.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.[CH3:22][N:23](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:22]#[N:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2cc(F)c[n+]3[O-])cc1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(F)cc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a solution of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine 4-oxide (2.4 g, 7.84 mmol) in 1,2-dichloroethane (60 mL) was added dimethylcarbamic chloride (1.3 g, 11.76 mmol), followed by addition of trimethylsilyl cyanide (1.2 g, 11.76 mmol). The mixture was stirred under nitrogen at 80° C. overnight. The resulting mixture was quenched by addition of a sat'd aq. NaHCO3 solution. The organic layer was washed with H2O (50 mL×3) and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (4:1) as eluent to afford 1.1 g (44.5%) of 6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile. MS (ESI) m/z: 316.1 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10](O)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>CN(C)C=O>[C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([Cl:19])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: CN(C)C=O
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
To a suspension of 2.2 g (10.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (202), Example 1a, Table 2) in 2.4 ml (55.0 mmol) of thionyl chloride is added one drop of dimethyl formamide and the mixture is stirred for 2 hours at room temperature. Excess thionyl chloride is afterwards distilled off on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system dichloromethane/hexane=1:1 and crystallisation of the pure fractions from methanol yields 0.30 g (13%) of 7-tert-butyl-3-chloro-5-methyl-3H-benzofuran-2-one, m.p. 81°-86° C. (compound (208), Table 2).
Reaction SMILES: C[O:2][C:3]([NH:5][C:6]([CH3:17])([CH2:9][CH2:10][C:11]1[S:12][C:13]([Br:16])=[CH:14][CH:15]=1)[CH2:7][OH:8])=O.CC(C)([O-])C.[K+]>CN(C)C=O>[Br:16][C:13]1[S:12][C:11]([CH2:10][CH2:9][C:6]2([CH3:17])[CH2:7][O:8][C:3](=[O:2])[NH:5]2)=[CH:15][CH:14]=1
Reactant: COC(=O)NC(C)(CO)CCc1ccc(Br)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(CCc2ccc(Br)s2)COC(=O)N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
2-Methoxycarbonylamino-2-methyl-4-(5-bromothiophen-2-yl)butan-1-ol (12.4 g, 38.6 mmol) obtained in Example 1(e) was dissolved in dimethylformamide (125 ml), and potassium t-butoxide (6.50 g, 57.9 mmol) was added thereto in an ice bath under a nitrogen atmosphere followed by stirring for 3 hours at the same temperature. The reaction mixture was poured into ice-cold 10% hydrochloric acid (300 ml), and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=4 1-1:2) to afford the title compound (10.7 g, 95% yield) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]2[CH2:23][C:22](=[O:24])[NH:21][C:18]2=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[C:17]3[CH2:23][C:22](=[O:24])[NH:21][C:18]3=[N:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1Cc2cc(Br)cnc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Cc2cc(-c3ccc(C(F)(F)F)cc3)cnc2N1
Temperature: 100 °C
Yield: 12.1 %

Procedure:
8.13 g 4-(Trifluormethyl)phenyl-boronic acid, 7.6 g 5-Bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one and 34.9 cesium carbonate were dissolved in a mixture of 14 ml water and 42 ml dimethylformamide. The reaction mixture was degassed with argon and then 2.0 g tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 100° C. for two hours. Then 1.0 g 4-(Trifluormethyl)phenyl-boronic acid were added and the mixture stirred for an additional hour. Then 1.0 g 4-(Trifluormethyl)phenyl-boronic acid were added and the mixture stirred for additional three hours at 100° C. The cooled reaction mixture was diluted with 500 ml ethyl acetate and washed with 300 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by chromatography on silica gel to obtain 1.2 g 5-(4-Trifluoromethyl-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:35]=[CH:34][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[CH:18][N:17]([CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21][C:22]([O:24]CC)=[O:23])[C:16]=3[CH:33]=2)=[O:10])=[CH:7][CH:6]=1)=[NH:3]>Cl>[NH2:3][C:2]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[CH:18][N:17]([CH:20]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:21][C:22]([OH:24])=[O:23])[C:16]=3[CH:33]=2)=[O:10])=[CH:34][CH:35]=1)=[NH:1]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccc(NC(=N)N)cc3)cc21
Agent: Cl
Product: N=C(N)Nc1ccc(C(=O)Nc2ccc3ncn(C(CC(=O)O)c4ccccc4)c3c2)cc1

Procedure:
A solution of ethyl 3-{6-[(4-{[amino(imino)methyl]amino}benzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (15 mg, 32 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 96 hours. The solution was then evaporated in vacuo, and the residue was purified by RP-HPLC to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=2.86 min, MH+ 443].