Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:6]1[NH:7][C:2](=[N:1][S:29]([CH3:28])(=[O:31])=[O:30])[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(C)N=C(N)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(=NS(C)(=O)=O)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 2-amino-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester (600 mg, 1.59 mmoles, see Example 2) in dichloromethane (5 ml) and pyridine (1.0 ml) was cooled to 0° C. under argon and was treated dropwise with methanesulfonyl chloride (0.42 ml, 5.26 mmoles). A catalytic amount of 4-dimethylamionpyridine was added and the reaction was allowed to warm to room temperature. After stirring overnight, the reaction was diluted with ethyl acetate and was washed with 1N hydrochloric acid, sodium bicarbonate and brine. It was dried over anhydrous magnesium sulfate and the solvent was evaporated to provide a colorless residue. Crystallization from ether-hexanes provided the title compound as a colorless crystalline material, melting point 139°-140.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:20])=[O:11])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C(N)=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (200 mg, 0.79 mmol) in 5 mL of dry tetrahydrofuran is added 1,1'-carbonyldiimidazole (167 mg, 1.03 mmol). The reaction solution is heated at reflux for 1 hour then cooled to room temperature. Aqueous ammonium hydroxide (3 mL) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with 1N HCl, saturated aqueous sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxamide in 84% yield; mp=154°-155° C.
Reaction SMILES: [C:1](/[C:3](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:4]([O:6][CH3:7])=[O:5])#[N:2].[N+]([CH:18]([CH3:20])[CH3:19])([O-])=O.C[O-].[Na+]>CO>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:18]1([CH3:20])[CH3:19])#[N:2]
Reactant: COC(=O)/C(C#N)=C/c1ccccc1
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C#N)C(c2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
A mixture of 511 mg (2.73 mmoles) of cyanoester 2 (produced in accordance with Example II), 0.25 mL (2.78 mmoles) of 2-nitropropane, and 2.64 mmoles of sodium methoxide (prepared from 61 mg of sodium and methyl alcohol) in 4.0 mL of absolute methanol was stirred at room temperature for 10 minutes and subsequently heated at reflux, protected from atmospheric moisture, for 71/2 hours. The product was isolated as described in the procedure of Example VIII, affording 483 mg (77% yield) of cyclopropanoid cyanoester 11, stereochemically homogeneous as shown by NMR analysis: δ3.83 (singlet, CO2CH3) and δ3.30 (singlet, cyclopropyl H).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([O:13]CC)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([S:22][C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[O:28][CH3:29])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([N:26]2[C@H:23]([S:22][C:19](=[O:21])[CH3:20])[C@@H:24]([O:28][CH3:29])[C:25]2=[O:27])[OH:13])=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(C)=O
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
714 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 4 g of molecular sieve A4 are added to a solution of 245 mg of (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 8 ml of toluene and 2 ml of dimethylformamide and the mixture is stirred overnight at room temperature. The molecular sieves are filtered off from the mixture and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel, and by elution with toluene/ethyl acetate (9:1 and 4:1) the title compound, contaminated with some glyoxylate, is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:12]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccnc2c1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: COc1ccc2cccnc2c1NS(=O)(=O)c1ccccc1
Yield: 33.3 %

Procedure:
In a similar fashion using route 14 general procedure 27, 7-methoxyquinolin-8-amine (Intermediate 64) (150 mg, 0.86 mmol), benzenesulfonyl chloride (130 μl, 1.03 mmol) and DMAP (cat.) gave the title compound (90 mg, 33%) after recrystallisation from DCM/n-pentane.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.F[C:19]1[C:24]([C:25]2([OH:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O.[Cl-].[Na+].O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[C:24]([C:25]3([OH:31])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: OC1(c2cccnc2F)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: OC1(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (0.123 g, 0.507 mmol) and 4-(2-fluoropyridin-3-yl)tetrahydro-2H-pyran-4-ol (0.1 g, 0.507 mmol) in DMSO (1 mL) was added cesium carbonate (0.330 g, 1.014 mmol). The resulting mixture was heated to 100° C. and stirred overnight. Aqueous work up with multiple water and brine washes to remove DMSO and extraction with DCM. Purification by Biotage (0-10% MeOH/DCM) produced product. MS (ESI, pos. ion) m/z: 420 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:15][CH2:14][C@@H:13]3[CH2:16][C@H:10]2[C:11](=O)[O:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:32][O:33][C:34]([CH2:36]P(OC)(OC)=O)=[O:35].Cl>C1COCC1.O>[CH3:32][O:33][C:34](=[O:35])/[CH:36]=[CH:11]/[C@@H:10]1[CH2:16][C@H:13]([OH:12])[CH2:14][CH2:15][N:9]1[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: C[C@H](c1ccccc1)N1CC[C@@H]2C[C@H]1C(=O)O2
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C/[C@@H]1C[C@H](O)CCN1[C@H](C)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 172.6 %

Procedure:
Dissolve 2.0 g (8.647 mmol) of (1S,5R)-2-[(1R)-1-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one [prepared from N-[(1R)-1-phenylethyl]but-3-en-1-amine according to Bioorg. Med. Chem. Lett. 6 (8), 964 (1996)] in 8 ml of abs. THF, cool to −78° C. and add 9.5 ml (9.5 mmol) of a 1M solution of L-Selectride in THF. After the end of the addition, continue stirring at −78° C. for 1 h, then warm to −20° C. and add 2.1 ml (13 mmol) of phosphonoacetic acid trimethyl ester. Then warm the reaction mixture to 0° C. and stir for 1 h. Water is then added and 1N hydrochloric acid is used to set a pH of approx. 7-8. Extract the mixture with dichloromethane three times, and combine the organic phases, dry over magnesium sulphate and concentrate under reduced pressure. 4.32 g of crude product are obtained, which are used without further purification in the next stage.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)(=[O:23])=[O:22]
Reactant: N#Cc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C#N)nc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
To a solution of 5-(hydroxymethyl)picolinonitrile (1.59 g, 11.9 mmol) in 80 mL of DCM was added diisopropylethylamine (3.2 mL), followed by a solution of methanesulfonyl chloride (1.49 g, 13.0 mmol) in 20 mL of DCM at 0° C. The solution was stirred at 0° C. for 40 min and washed with 5% citric acid, sat. NaHCO3 (aq.) and brine. After concentration, the residue was purified by silica gel chromatography (elution with 0-30% EtOAc/Hex) to afford (6-cyanopyridin-3-yl)methyl methanesulfonate (2.33 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>N1C=CC=CC=1>[C:8]1([C:5]2[CH:4]=[C:3]([CH2:2][NH:1][C:15](=[O:16])[O:17][CH2:18][CH3:19])[O:7][N:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCc1cc(-c2ccccc2)no1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 7 g. portion of the product of Example 8 was dissolved in 50 ml. of pyridine, cooled in an ice bath, and combined with 10 ml. of ethyl chloroformate. The mixture was stirred at ice bath temperature for 1 hour and allowed to warm to room temperature while being stirred for 2 hours more. The mixture was then poured into ice water and the crude product was separated by filtration and purified by chromatography over silica gel with ethyl acetate as the eluent. The yield was 6 g. of purified [(3-phenyl-5-isoxazolyl)-methyl]carbamic acid, ethyl ester, m.p. 82°.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27](Cl)=[O:28]>C(Cl)Cl>[N+:33]([C:32]1[CH:31]=[CH:30][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:28])=[CH:25][C:24]=1[O:23][CH3:22])([O-:35])=[O:34]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
To a solution of 0.55 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.55 g of triethylamine followed by 0.97 g of 3-methoxy-4-nitrobenzoyl chloride. The reaction mixture is stirred at room temperature for 2 hours and then quenched with 10 ml of 1N NaOH. The methylene chloride layer is evaporated and the resulting suspension filtered. The precipitate is washed with 1N NaOH (2×5 ml), water (3×5 ml) and hexane (2×5 ml). The collected solid is dried in vacuo to give 1.13 g of off-white solid. MS(CI): 364(M+H).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]=O.BrC[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH2:13][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=CNc1nc2ccccc2s1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1nc2ccccc2s1
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To the suspension of 0.2 g (5 mmol) 60% sodium hydride in 5 ml dimethylformamide in small portions 0.89 g (5 mmol) 1,3-benzothiazol-2-ylformamide, then after 30 minutes of stirring, dropwise the solution of 0.92 g (5.5 mmol) ethyl bromoacetate in 2 ml dimethylformamide are added and the mixture is stirred at room temperature for 4 hours. The reaction mixture is poured onto ice-water mixture, the precipitated crystals are filtered off. 0.85 g title compound is obtained. LC/MS[MH+]=237 (C11H12N2O2S 236.294). The mixture of N2-1,3-benzothiazol-2-yl-N1-{3-[(3,4-dichlorobenzyl)(methyl)amino]propyl}glicinamide 0.68 g (2.88 mmol) ethyl N-1,3-benzothiazol-2-ylglicinate and 0.81 g (2.88 mmol) N-(3,4-dichlorobenzyl)-N-(methyl)propane-1,3-diamine is heated at 100° C. for 2 hours. The crude melt is purified by column chromatography using chloroform-methanol 19:1 mixture as eluent. 500 mg title compound is obtained as crystals.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH3:14])[CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[CH:29][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:19]=[CH:20][CH:21]=1.C([O-])(O)=O.[Na+].N#N>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:13][CH2:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([C:23](=[O:24])[CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[CH:17]=2)[CH2:26][CH2:27]3)=[CH:3]1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Reactant: COCn1cc(Br)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: COCn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(C)c2)c2c(N)ncnc21
Temperature: 100 °C
Yield: 33.3 %

Procedure:
To 5-bromo-7-[(methyloxy)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (65 mg, 0.253 mmol), and 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (114 mg, 0.303 mmol) were dissolved in 1,4-Dioxane (2 mL) was added saturated NaHCO3 (1 mL). The mixture was then bubbled N2 gas for 10 min then added Pd(Ph3P)4 (29.2 mg, 0.025 mmol) then bubbled for 5 additional minutes. The reaction was then capped and heated at 100° C. overnight. The mixture cooled then diluted with water (10 mL) and extracted with EtOAc (3×20 ml). The organics were combined, washed with brine, dried over MgSo4, filtered and concentrated to afford an amber color oil. The oil was then purified on a 10 g Biotage SNAP column conditioned with Hexane using a gradient of 0 to 10% MeOH in DCM for 30 minutes to isolate 7-[(methyloxy)methyl]-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (36 mg) as a white solid. LC-MS (ES) m/z=428.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 7.37 (s, 1H), 7.32-7.35 (m, 1H), 7.24 (dd, J=7.33, 14.65 Hz, 2H), 7.06-7.15 (m, 3H), 6.15 (br. s., 2H), 5.50 (s, 2H), 4.21 (s, 2H), 3.83 (s, 2H), 3.25 (s, 3H), 3.19-3.25 (m, 2H), 2.31 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].I[CH:28]([CH3:30])[CH3:29]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH:28]([CH3:30])[CH3:29])=[CH:20][CH:21]=1
Reactant: CC(C)I
Reactant: COC(=O)Cc1c(C(=O)c2ccc(O)cc2)[nH]c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C(=O)c2ccc(OC(C)C)cc2)[nH]c2cc(Cl)ccc12
Reaction time: 0.08 h
Yield: 42.4 %

Procedure:
To a stirred solution of methyl[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate (Example 183, 0.15 g, 0.44 mmol) in DMF (5 ml) was added sodium hydride (15 mg, 0.46 mmol) at room temperature under nitrogen atmosphere. After 5min., 2-iodopropane (78 mg) was added and the mixture was stirred for 7 h. The mixture was quenched with 2N aqueous HCl (20 ml), and extracted with ethyl acetate (50 ml). The extract was washed with water (30 ml) and brine (30 ml), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate-hexane (1:2) to afford 72 mg (43%) of the title compound as white solids.
Reaction SMILES: [Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[N:6]=[C:7](Cl)[NH:8][C:4]=2[CH:3]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:5]2[NH:6][C:7]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([C:17]([F:31])([F:16])[F:30])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1cc2nc(Cl)[nH]c2cc1Br
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: FC(F)(F)c1cc2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2cc1Br

Procedure:
The benzoimidazole from step (f) above (1.2 g, 4.0 mmol) reacted with 1-(3-trifluoromethylpyridin-2-yl)piperazine (1.4 g, 6.0 mmol, Oakwood) under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 496.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][C:17]([CH3:25])([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:6][CH:7]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)[CH3:28]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CC(C)(C)c1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CC(C)(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,3-dimethyl-3-phenyl-butyl)-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [ClH:1].[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:14]([OH:16])=O)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+:10]([O-:12])=[O:11].[Cl:24][C:25](OCC(C)C)=O.CN1CCOCC1.[N+](=C)=[N-].N(C(OC(C)(C)C)=O)[C@H](C(C=[N+]=[N-])=O)CCCNC(=N)N[N+]([O-])=O>O1CCCC1.C(O)C.C(OCC)C.C(O)(=O)C>[NH2:2][C@H:3]([C:14]([CH2:25][Cl:24])=[O:16])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:13])[NH:9][N+:10]([O-:12])=[O:11].[ClH:1]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: C=[N+]=[N-]
Agent: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)C=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: N=C(NCCC[C@H](N)C(=O)CCl)N[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
HCl. Boc-L-Arg(NO2)OH (5.00 g, 15.6 mmol) was dissolved in tetrahydrofuran (THF) (200 ml) and treated with isobutyl chloroformate (2.06 g, 15.6 mmol) in the presence of N-methylmorpholine (1.72 ml, 15.6 mmol) for 10 min at 0° C. The mixed anhydride preparation was filtered, and the filtrate was added to ethereal diazomethane [120 ml prepared from Diazald (5.4 g, 25 mmol)] over a period of 5 min. After the reaction was stirred at 0° C. for 45 min, acetic acid (0.5 ml) was added to quench the excess diazomethane. The product crystallized from the reaction mixture. The solvent was removed, and the residue was diluted with chloroform (25 ml). The crystalline product, Boc-L-Arg(NO2)CHN2, was filtered and dried in vacuo. Boc-L-Arg(NO2)CHN2 (3.97 g, 11.5 mmol) was dissolved in ethanol (23 ml) and cooled to 0° C. HCl (12.5 ml of a 10% solution in ethanol) was added dropwise over a period of 20 min. After the reaction mixture was stirred at room temperature (RT) for 1 hr, it was poured into diethyl ether (400 ml). The solution was allowed to stand for 2 hr at 5° C., filtered under N2, and dried in a vacuum desiccator to afford 1.72 g H-L-Arg(NO2)CH2Cl.HCl as a white powder. The product was characterized by 360 MHz 1H NMR.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=[O:28].[Cl-].[NH4+]>CCCCCC.C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([CH:27]([OH:28])[C:13]2([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: O=Cc1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(Br)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
42.2 ml (105.5 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution, cooled to from −20° C. to −30° C., of 14.8 ml (105.5 mmol) of diisopropylamine in 60 ml of abs. THF. After the addition had ended, the mixture was stirred at from −20° C. to −30° C. for another 30 min. The mixture was then cooled to −78° C., and a solution of 12.0 g (84.4 mmol) of tert-butyl cyclopropanecarboxylate in 60 ml of abs. THF was added dropwise at this temperature. After 4 h at −78° C., a solution of 15.4 g (70.3 mmol) of 3-bromo-4-chlorobenzaldehyde in 60 ml of abs. THF was added. The reaction mixture was slowly warmed to RT overnight, saturated aqueous ammonium chloride solution was then added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1→10:1). This gave 16.2 g of the target compound (52.5% of theory).