Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[CH3:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:47]([C:43]2[N:42]([CH3:41])[CH:46]=[CH:45][N:44]=2)(=[O:49])=[O:48])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: Cn1ccnc1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2nccn2C)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.13 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and 1-methyl-1H-imidazole-2-sulfonyl chloride (136 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 229 mg, 98%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:26][C:27]1[S:28][C:29](CCl)=[CH:30][CH:31]=1.Cl>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[S:28][C:27]([Cl:26])=[CH:31][CH:30]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: ClCc1ccc(Cl)s1
Agent: Cl
Product: Clc1ccc(CSc2c(Cl)ccc3c2CCNCC3)s1

Procedure:
Use a method similar to the Example 387, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-chloro-5-(chloromethyl)thiophene to give, after hydrochloride formation by the General Procedure 2-2, the title compound as a brown solid. MS (APCI+) m/z: 344 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[N:29][C:5]2[N:6]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[CH:9][CH:8]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58]O)[CH2:53][CH2:52]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C1COCC1.CO>[Cl:1][C:2]1[CH:30]=[N:29][C:5]2[N:6]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:58][CH2:57][N:54]2[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]2)=[CH:15][CH:14]=1)=[CH:9][CH:8]=3
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(O)cc3)cc2c2cc(Cl)cnc21
Reactant: CN1CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccc(-c3ccc4c(c3)c3cc(Cl)cnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (240 mg, 0.55 mmol, 1 equiv.) in anhydrous THF (14 ml), triphenylphosphin (577 mg, 2.2 mmol, 4 equiv.) and 2-(4-methylpiperazin-1-yl)ethanol (397 mg, 2.75 mmol, 5 equiv.) are added. DIAD (445 mg, 2.2 mmol, 4 equiv.) is then added dropwise to the solution which is stirred at room temperature for 12 hours. The mixture is then extracted with a solution of HCl 0.1M (3×10 ml). The aqueous layer is treated with Na2CO3 until pH=9 and then extracted with AcOEt (3×20 ml). The organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue (yellow solid) is purified over silica chromatography (eluted with AcOEt/MeOH 9:1 and then THF/MeOH 9:1) to give the product as a white solid (259 mg, 0.44 mmol) in 80% yield. 1H NMR (300 MHz, CDCl3) δ 8.47 (dd, 2H, J=2.5, 7.7 Hz), 8.17 (d, 1H, J=2.1 Hz), 8.13 (d, 2H, J=7.5 Hz), 8.00 (d, 1H, J=0.9 Hz), 7.76 (dd, 1H, J=1.5, 8.6 Hz), 7.57-7.39 (m, 5H), 7.55 (d, 2H, J=8.6 Hz), 7.01 (d, 2H, J=8.5 Hz), 4.17 (t, 2H, J=5.6 Hz), 2.87 (t, 2H, J=5.6 Hz), 2.70-2.58 (br d, 8H), 2.35 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25]>C(#N)C>[CH2:10]([O:9][C:7]([C:4]1[CH:3]=[C:2]([O:1][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[NH:6][N:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cc(O)[nH]n1
Reactant: O=C1CCCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OC2CCCCC2=O)[nH]n1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (6.25 g, 40 mmol) and 22.1 g of potassium carbonate in 500 ml of acetonitrile was added 6.35 g of 2-chlorocyclohexanone, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. The product was purified by silics-gel column chromatography by eluting it with 1:1 ethyl acetaet;hexane. 4.92 g (49%) of the desired product was obtained as a white solid. M.Pt. 122–124° C.; (M+H) 253.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:32]3[N:31]([CH3:30])[C:39]4[C:34]([CH:33]=3)=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: Cn1c(C=O)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3cc4ccccc4n3C)CC1)O2
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) in 1 M Na2CO3, was stirred for 10 minutes, then extracted with DCM and treated with N-methyl-indol-2-carbaldehyde (95 mg, 0.60 mmol) and sodium triacetoxyborohydride (159 mg, 0.750 mmol) following the procedure described in Example 55, Step A, giving (E)-3-{1′-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (179 mg) as a white solid. The resulting ester was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (187 mg) as an orange solid (hydrochloride salt). The product was suspended in DCM (3 ml), TEA (0.08 ml, 0.58 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (37 mg) as a light yellow solid. The compound was then dissolved in DCM (3 ml) and treated with 4 M HCl in dioxane (0.1 ml, 0.4 mmol) as described in Example 55, Step D, giving a light yellow solid after aqueous workup and column chromatography (eluent:DCM/MeOH 99:1 to 95:5) (7 mg, free base)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=O)([CH3:7])[CH3:6])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[CH:16]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 77.9 %

Procedure:
2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (7 g, 26 mmol) and 6-chlorooxindole (3.6 g, 22 mmol) were mixed in anhydrous methanol (30 mL) at room temperature. Then pyrrolidine (1.85 g, 26 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g).
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:39])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]3=4)=[O:26])=[CH:21][C:20]=2[CH3:38])[C:10]2[C:40]([F:44])=[CH:41][CH:42]=[CH:43][C:9]1=2)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:40]1[C:10]2[N:11]([C:16](=[O:39])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]5[CH:34]=[CH:35][CH:36]=[CH:37][C:28]4=5)=[O:26])=[CH:21][C:20]=3[CH3:38])[CH2:12][CH2:13][C:14](=[O:15])[N:8]([CH2:7][C:6]([OH:45])=[O:5])[C:9]=2[CH:43]=[CH:42][CH:41]=1
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(F)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CCC(=O)N(CC(=O)O)c2cccc(F)c21
Reaction time: 1.5 h

Procedure:
To a solution of {6-fluoro-5-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylcabamoyl]-2-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]acetic acid tert-butyl ester from Example 1 (250 mg, 0.40 mmol) in dichloromethane (8 ml) was added trifluoroacetic acid (8 ml). The mixture was stirred for 90 min and evaporated in vacuo and azeotroped with toluene to give an off-white solid; yield 220 mg, 99%.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]1[C:8]([CH:17]=[O:18])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1>C(Cl)Cl>[OH:6][C:7]1[C:8]([CH:17]=[O:18])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1
Reactant: COc1cc2c(cc1C=O)OCCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1cc2c(cc1O)OCCO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4 eq. of AlCl3 are suspended in 10 ml of anhydrous CH2Cl2. Under an inert atmosphere, 100 mg (5.55 mmol) of the compound obtained in Step C, dissolved in 10 ml of anhydrous CH2Cl2, are added to that mixture and allowed to act for 2 hours at ambient temperature. The mixture is hydrolysed with an ice-cold 2N HCl solution; the solution is then extracted with CH2Cl2 and dried over MgSO4. After evaporation of the solvent, purification on a silica column (eluant:PE/AcOEt 7/3) is carried out and the pure product is isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Yield: 77.1 %

Procedure:
As described for Example 9, 0.942 g (3 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.52 g (3.3 mmol) of 2-methylbenzoyl chloride in 20 ml of dichloromethane. The product is triturated with hexane-ethyl acetate to give 1.0 g of yellow crystals, m.p. 198°-203° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8]OS(C)(=O)=O)=[C:5]([CH3:14])[N:4]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:3]=1.[CH3:25][O:26][C:27](=[O:41])/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([C@@H:36]2[CH2:40][CH2:39][CH2:38][NH:37]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C(=O)C>[CH3:25][O:26][C:27](=[O:41])/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([C@@H:36]2[CH2:40][CH2:39][CH2:38][N:37]2[CH2:8][CH2:7][C:6]2[C:2]([CH3:1])=[N:3][N:4]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[C:5]=2[CH3:14])=[CH:32][CH:31]=1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c(CCOS(C)(=O)=O)c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)nn(S(=O)(=O)c3ccc(C)cc3)c2C)cc1
Yield: 60.8 %

Procedure:
To a mixture of methanesulfonic acid 2-[3,5-dimethyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-ethyl ester (600 mg, 1.61 mmol) and (E)-3-((S)-4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (317 mg, 1.37 mmol) in 10 mL acetonitrile-N,N-dimethylacetamide (3:1 v/v) was added potassium carbonate (334 mg, 2.42 mmol). The mixture was subjected to microwave irradiation for 15 minutes and the crude mixture was filtered through a plug of Celite, which was washed with dichloromethane. The combined filtrates were partially concentrated and partitioned between ethyl acetate and aqueous ammonium chloride solution. The organic layer was washed three times with the same salt solution, which was back extracted once. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give a yellow oil, which was purified via silica gel column chromatography (0-50% ethyl acetate in heptane) to give ((E)-3-[4-((S)-1-{2-[3,5-dimethyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-ethyl}-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (423 mg, 0.833 mmol, 52% yield) as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][S:12][CH3:13])[CH:5]=1.[OH:14]O>C(O)(=O)C.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>[CH3:13][S:12]([CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:2][CH3:1])=[O:14]
Reactant: CNCc1cccc(OCSC)c1
Reactant: OO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCc1cccc(OCS(C)=O)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Compound from step 3 (592 mg, 3.00 mmol) was dissolved in glacial acetic acid (4 mL) and cooled to 0° C. H2O2 (0.34 mL, 3.00 mmol) was added drop-wise. The mixture was allowed to stir for 6 h. The mixture was then diluted with CH2Cl2 and neutralized with K2CO3. The solids were filtered off. The filtrate was dried over Na2SO4 and concentrated in vacuo to give 640 mg (quant) of a yellow crystalline solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]1[O:40][C:39]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=2[O:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:33]1[C:34]2[CH:35]=[CH:36][C:37]([N:18]3[C:19]4[C:15](=[CH:14][C:13]([C:11]([N:8]5[CH2:7][CH2:6][N:5]([CH:1]6[CH2:2][CH2:3][CH2:4]6)[CH2:10][CH2:9]5)=[O:12])=[CH:21][CH:20]=4)[CH:16]=[C:17]3[C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:38][C:39]=2[O:40][CH2:32]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc2c(c1)OCO2)N1CCN(C2CCC2)CC1
Yield: 24 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3,4-methylenedioxybenzeneboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (24%).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:14]=3[N:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N:24]1(C(OC(C)(C)C)=O)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[N:24]1([C:21]([C:19]2[CH:18]=[CH:17][C:15]3[NH:16][C:12]([C:11]4[C:2](=[O:1])[NH:3][C:4]5[C:9]([CH:10]=4)=[CH:8][CH:7]=[CH:6][CH:5]=5)=[N:13][C:14]=3[CH:20]=2)=[O:23])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)nc2c1)N1CCNCC1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A mixture of 2-(2-oxo-1,2-dihydro-3-quinolinyl)-1H-benzimidazole-5-carboxylic acid (4-6, 130 mg, 0.43 mmol, 1 equiv, tert-butyl l-piperazinecarboxylate (79 mg, 0.43 mmol, 1.0 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97 mg, 0.51 mmol, 1.2 equiv), 1-hydroxy-7-azabenzotriazole (70 mg, 0.51 mmol, 1.2 equiv), and triethylamine (0.148 mL, 1.06 mmol, 2.50 equiv) in DMF (5.0 mL) was stirred at 23° C. for 20 h. The reaction mixture was partitioned between water (50 mL) ethyl actate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. A solution of the residue, DMSO (10 uL), and water (10 uL) in a 1:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred at 23° C. for 45 min. The reaction mixture was concentrated, and the residue was purified by reverse-phase liquid chromotography (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated sodium bicarbonate solution (50 mL) and a 10% solution of methanol in dichloromethane (2×50 mL) to provide 3-[5-(1-piperazinylcarbonyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinone (14-1) as its free base. 1H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.59 (s, 1H), 7.74 (m, 2H), 7.53 (m, 2H), 7.39 (m, 2H), 7.26 (m, 2H), 3.61 (br m, 1H), 3.60 (br m, 1H), 3.32 (br m, 1H), 1.98 (br m, 1H), 1.89 (br m, 1H), 1.62 (br m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.[C:13]1([O:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>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>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:22]2)=[O:12]
Reactant: C#CCOc1ccccc1
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Resin bound 4-amino-3-iodo-benzoic acid methyl ester was suspended in DMF and treated with 15.6 g of phenyl propargylether, 60 ml of triethylamine and catalytic amounts of Cul and bis(triphenylphosphine)palladium(II) chloride. The resin was shaken for 6 h at 50° C. and washed subsequently with DMF, isopropanol/water and diethylether.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5]C(=O)OCC1C=CC=CC=1.[H][H]>CO>[NH2:5][CH2:4][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:2][OH:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(CO)CNC(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl tert-butyl (3-hydroxypropane-1,2-diyl)biscarbamate (400 mg, 1.23 mmol) was dissolved in methanol (12.3 mL) and put under a hydrogen atmosphere with 3 cycles of evacuation and hydrogen balloon flushing. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours, and then filtered through CELITE. The filtrate was concentrated under reduced pressure to afford tert-butyl 1-amino-3-hydroxypropan-2-ylcarbamate. MS ESI calcd. for C8H19N2O3 [M+H]+ 191. found 191. 1H NMR (500 MHz, CDCl3) δ 5.25 (s, 1H), 3.87 (d, J=10.0 Hz, 1H), 3.71 (d, J=10.5 Hz, 1H), 3.59-3.63 (m, 1H), 3.08 (d, J=10.6 Hz, 1H), 2.90 (d, J=10.1 Hz, 1H), 1.84 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:39])[NH:33][CH2:34][C@H:35]([NH2:38])[CH2:36][OH:37])([CH3:30])([CH3:29])[CH3:28].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:38][C@H:35]([CH2:36][OH:37])[CH2:34][NH:33][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:39])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NC[C@H](N)CO
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.18 g (0.49 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.122 g (0.64 mmol) of tert-butyl[(2S)-2-amino-3-hydroxypropyl]carbamate (Example 251A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.123 g (0.64 mmol) of EDC and 0.02 g (0.15 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is purified by preparative HPLC (Kromasil, mobile phase acetonitrile/0.25% aqueous trifluoroacetic acid 5:95→95:5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:18]1[CH:17]=[N:16][C:15]([Cl:14])=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1ccc(Cl)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccc(Cl)nc1

Procedure:
A 950 mg (5.1 mmol) sample of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, prepared as in Example 7b above, and 550 mg (4.25 mmol) of 2-chloro-5-hydroxypyridine were reacted with triphenylphosphine and DEAD (5.1 mmol each) in 20 mL of THF according to the procedure of Example 14a, to give 1.09 g of the title compound. MS (DCI/NH3) m/e: 299/301 (M+H)+. 1H NMR (DMSO-d6, 300 MHz) δ: 8.14 (d, J=3.3 Hz, 1H), 7.48 (dd, J=8.8, 3.3 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.47-4.42 (m, 1H), 4.36 (dd, J=11.0, 4.4 Hz, 1H), 4.20 (dd, J=11.0, 3.3 Hz, 1H), 3.77 (t, J=7.7 Hz, 2H), 2.36-2.29 (m, 1H), 2.19-2.12 (m, 1H), 1.36 (s, 9H). [α]D25 =-67.3° (c=1.1, CHCl3).