Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C:14]1[C:15]2[C:22]([C:23]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([NH2:31])[CH:30]=3)=[O:24])=[CH:21][N:20]([CH:32]([CH3:34])[CH3:33])[C:16]=2[N:17]=[CH:18][N:19]=1>N1C=CC=CC=1>[NH2:13][C:14]1[C:15]2[C:22]([C:23]([C:25]3[CH:30]=[C:29]([NH:31][S:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)(=[O:11])=[O:10])[CH:28]=[N:27][CH:26]=3)=[O:24])=[CH:21][N:20]([CH:32]([CH3:34])[CH3:33])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2c(N)ncnc21
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cncc(NS(=O)(=O)c3cc(F)cc(F)c3)c2)c2c(N)ncnc21
Temperature: 40 °C

Procedure:
3,5-Difluoro-benzenesulfonyl chloride (19.7 mg, 0.093 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (25 mg, 0.084 mmol) in pyridine (0.7 mL). The resulting solution was heated to 40° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue dissolved in DMSO (2 mL) and purified using reverse phase preparative HPLC to furnish the title compound as a white solid. MS: 473.2 (MH+); HPLC Rf: 4.91 min. (HPLC method 4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I>CCOCC.CC#N>[CH3:1][O:2][C:3](=[O:9])[CH2:4][O:5][CH2:6][CH2:7][I:34]
Reactant: II
Reactant: COC(=O)COCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)COCCI
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To solution of methyl(2-hydroxyethoxy)acetate (540 mg), imidazole (411 mg) and triphenylphosphine (1.37 g) in ether (2 mL) and CH3CN (1 mL) was added iodine (1.43 g) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. After insolubles were filtered off, the filtrates were diluted with AcOEt, washed with aq Na2SO3 solution and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-5:1) to give methyl(2-iodoethoxy)acetate as colorless oil (898 mg).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH:14]([CH2:18][CH3:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH:14]([CH2:18][CH3:19])[CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: CCC1CN(c2nn(N)c(=O)c3ccccc23)CCO1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: CCC1CN(c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)CCO1

Procedure:
The product from Example 220B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H), 8.29 (dd, J=7.8, 1.2 Hz, 1H), 7.96-8.03 (m, 2H), 7.90 (ddd, J=7.9, 6.7, 1.4 Hz, 1H), 7.40-7.41 (m, 4H), 3.91 (dd, J=11.1, 2.6 Hz, 1H), 3.79 (td, J=11.4, 2.3 Hz, 1H), 3.67 (s, 2H), 3.56-3.65 (m, 1H), 3.26-3.32 (m, 2H), 2.76-2.84 (m, 1H), 2.51-2.57 (m, 1H), 1.48 (p, J=7.1 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H); MS (DCI+) M/Z 427 (M+H)+, 444 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(B(CC)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(O)C.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>[OH:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Oc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
3-bromophenol (49.42 g, 285.66 mmol) and diethyl-(3-pyridyl)borane (40.00 g, 272.05 mmol) were dissolved in 945 mL of a 4:2:1 mixture of THF/H2O/ethanol in a 2 L round bottom flask equipped with a magnetic stirrer. Sodium carbonate (57.7 g, 544.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.14 g, 2.72 mmol) was added and the mixture was heated at reflux for 2 h then cooled to ambient temperature and stirred an additional 18 h. The mixture was diluted with 400 mL water and extracted with ethyl acetate (3×500 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to a volume of 1 L. The organic solution was diluted with 500 mL water and made acidic with 12N HCl. The layers were separated and the organic phase extracted with water (2×300 mL). The acidic extractions were combined and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with diethyl ether (3×500 mL) and the extracts were combined, washed with 500 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 40.91 g (88%) of 3-(3-hydroxyphenyl)pyridine as a pale yellow oil which crystallized on standing.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:12]([OH:27])[C:13]([N:15]1[CH2:26][CH2:25][CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].[CH2:35]([O:42][C:43]([NH:45][C:46]1[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=1)[O:49][CH2:50][C:51](O)=[O:52])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]([NH:45][C:46]1[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=1)[O:49][CH2:50][C:51]([NH:2][C@H:3]([C:8]([NH:10][C@@H:11]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:12]([OH:27])[C:13]([N:15]1[CH2:26][CH2:25][CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])=[O:52])=[O:44])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)COc1cccc(NC(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: Cl
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1cccc(NC(=O)OCc2ccccc2)c1
Yield: 50.2 %

Procedure:
Following a procedure similar to that described in Example 14, but using 0.45 g (0.91 mmol) of 1-[(2S,3S)-3-L-asparaginylamino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide hydrochloride and 0.30 g (1.00 mmol) of 3-benzyloxycarbonylaminophenoxyacetic acid, 0.34 g of the title compound were obtained as a colorless powder, melting at 107°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH:9][CH2:10][CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](O)=[O:13])[CH:6]([CH3:8])[CH3:7])=[O:4].CN1CCOCC1.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=O)=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]([N:9]1[CH2:10][CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1=[O:13])[CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: COC(=O)C(NCC(NC(=O)Cc1ccccc1)C(=O)O)C(C)C
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)C(C(C)C)N1CC(NC(=O)Cc2ccccc2)C1=O
Reaction time: 18 h
Yield: 1.1 %

Procedure:
3-(1-Methoxycarbonyl-2-methylpropylamino)-2-(2-phenylacetamido)propionic acid (0.92 g) was dissolved in ethyl acetate (100 ml), and to the solution, there were added 4-methylmorpholine (0.66 g) and 1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole (1.11 g) under ice-cooling. The mixture was stirred at the same temperature for 18 hours and the insoluble materials were removed by filtration from the reaction mixture and ice-water (30 ml) was poured into the filtrate, whereafter the resultant mixture was stirred enough. The ethyl acetate layer was separated from the mixture, washed three times with an aqueous sodium bicarbonate and once with water, and then dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (15 g). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation from the eluate under reduced pressure to give 1-(1-methoxycarbonyl-2-methylpropyl)-3-(2-phenylacetamido)-2-azetidinone (10 mg), mp 105° to 107° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:13][N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=12>>[CH3:1][O:2][C:5]1[N:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:13][N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: C[O-]
Reactant: Clc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Product: COc1nnccc1-c1c(-c2ccccc2)nn2ccccc12

Procedure:
To a 28% methanolic solution of sodium methoxide (3 ml) was added 3-(3-chloropyridazin-4-yl)-2-phenylpyrazolo[1.5-a]pyridine (0.61 g). The mixture was refluxed for an hour and evaporated in vacuo. The residue was dissolved in chloroform (20 ml). The chloroform solution was washed with water (5 ml) and a saturated aqueous solution of sodium chloride (5 ml) and dried over magnesium sulfate. The solvent was removed and chromatographed on silica gel (10 g) with n-hexane-ethyl acetate as an eluent. The fractions containing the object compound were combined, evaporated in vacuo, and then recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(3-methoxypyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.30 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12])([O-])=O.B.C1COCC1.Cl>>[NH2:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCCc1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of (2-nitrophenyl)acetonitrile (3 g, 18.5 mmol) was added dropwise a 1 M BH3-THF solution (125 mL) at 0° C. After 4 h of stirring at 25° C., 6N HCl solution (125 mL) was added to the reaction mixture at 0° C. After evaporation of the organic solvent in vacuo, the aqueous phase was basified with 4N NaOH solution to pH 10. Then the product was extracted with EtOAc and the organic phase was dried over MgSO4 and concentrated in vacuo. A brown liquid (41, 2 g, 10.8 mmol) was isolated. Without further purification, it was mixed with SnCl2 2H2O (13.57 g, 60.2 mmol) and absolute ethanol (20 mL). The suspension was heated at 70° C. under nitrogen. After being stirred for 30 min, the starting material disappeared, the solution was allowed to cool, then poured into ice (100 g). The pH was made slightly basic (pH 8) by the addition of a 5% aqueous NaHCO3 solution, and the resulting basic mixture was stirred for 1 h. The precipitate was extracted with ethyl acetate (100 mL×3). The extract was washed with water (50 mL×3) and dried over MgSO4. The product was obtained in a yield of 52% (1.3 g, brown liquid, over two steps) after evaporation of the solvent: 1H NMR (400 MHz, CD3OD) δ6.97 (t, J=7.2 Hz, 2H), 6.72 (d, J=7.2 Hz, 2H), 6.64 (t, J=7.2 Hz, 1H), 2.82 (t, J=7.2 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H). HRMS (EI) m/z (M+) calcd for C8H12N2 136.1000, found 136.1002.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:58]([C:60]1[CH:68]=[C:67]([CH3:69])[C:63](C(O)=O)=[C:62]([CH3:70])[CH:61]=1)#[N:59].CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CN(C=O)C>[C:58]([C:60]1[CH:68]=[C:67]([CH3:69])[C:63]([C:6]([NH:7][CH2:8][CH2:9][C@H:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=3)[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)[CH3:11])=[O:5])=[C:62]([CH3:70])[CH:61]=1)#[N:59]
Reactant: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1cc(C#N)cc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C#N)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
(R)-(3-{4-[(6-Cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.070 g, 0.14 mmol) was dissolved in a 3:1 mixture of CH2Cl2 and TFA and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the resulting brown oil dried in vacuo (high vacuum system) for 2 h. The resulting amine, EDCI (0.030 g, 0.0.16 mmol) and HOBT (0.021 g, 0.16 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 4-cyano-2,6-dimethyl-benzoic acid (0.027 g, 0.16 mmol) followed by DIPEA (163 μL, 0.94 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded 4-cyano-N-((R)-3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (0.043 g, 55%) as a white foam. 1H NMR (CDCl3) δ 0.90 (m, 1H), 0.98 (d, 3H, J=6.0 Hz), 1.09 (m, 1H), 1.53 (m, 1H), 1.73 (m, 3H), 2.10 (br t, 1H), 2.37 (s, 6H), 2.51 (br t, 1H), 2.69 (m, 1H), 2.81-2.85 (m, 2H), 3.30-3.37 (m, 2H), 3.72 (s, 3H), 3.84 (m, 1H), 3.92 (s, 2H), 6.63 (d, 2H, J=9.0 Hz), 6.75 (d, 2H, J=9.0 Hz), 7.37 (s, 2H), 7.42 (d, 1H, J=6.0 Hz), 7.53 (d, 1H, J=9.0 Hz), 7.69 (t, 1H, J=9.0 Hz), 8.48 (br s, 1H). ES-MS m/z 551 (M+H), 573 (M+Na). Anal. Calcd. for C33H38N6O2.0.1 CH2Cl2: C, 71.10; H, 6.89; N, 15.03. Found: C, 71.17; H, 7.01; N, 15.00.
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(C([Cl:21])=O)=O>C(Cl)Cl>[C:4]1([CH2:3][CH2:2][C:1]([Cl:21])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
A 200 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with hydrocinnamic acid (5.00 g, 33.3 mmol), DMF (0.1 mL), and CH2Cl2 (30 mL). To the resultant solution was added (COCl)2 (2M in CH2Cl2, 20.0 mL, 40.0 mmol) over 30 min. The mixture stirred overnight at rt, and then was concentrated in vacuo to give 5.9 g of 74 as a yellow oil (100%). HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with a retention time of 5.3 min.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:16]([F:22])([F:21])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH:16]([F:22])[F:21])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(OC(F)F)c(Br)cc21
Reaction time: 3 h

Procedure:
1-Acetyl-6-bromo-5-hydroxyindoline (2 g, 7.8 mmol), methyl 2-chloro-2,2-difluoroacetate (0.82 ml, 7.8 mmol) and potassium carbonate (1.08 g, 7.8 mmol) were suspended in N,N-dimethylformamide (20 mL) under an argon atmosphere and placed in a 65° C. oil bath. After 3 hr, additional methyl 2-chloro-2,2-difluoroacetate (0.3 ml, 2.8 mmol) and potassium carbonate (0.3 g, 2.2 mmol) was added and heated for 18 hr. The solvent was then removed in vacuo and the residue was partitioned between cold 3N HCl and ether. The aqueous layer was extracted three times with ether, the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The solid was purified by flash chromatography (2% MeOH/CH2Cl2) to provide the title compound as a white solid
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[C:18]=1[F:19].[OH:20][CH2:21][C:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH2:23][CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:18]1[C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=[CH:3][C:2]=1[O:20][CH2:21][C:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])([CH3:27])[CH2:23][CH:24]([CH3:25])[CH3:26])=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15]
Reactant: Cc1nccc2c1c(=O)n(C)c1c(F)c(Br)ccc21
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1nccc2c1c(=O)n(C)c1c(F)c(OCC(C)(CC(C)C)NC(=O)OC(C)(C)C)ccc21
Temperature: 100 °C

Procedure:
To a stirred solution of 8-bromo-7-fluoro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (350 mg, 1.090 mmol) and tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (504 mg, 2.180 mmol) in toluene (10 mL) was added cesium carbonate (355 mg, 1.09 mmol) and 2-Di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (28 mg, 0.065 mmol). The reaction mixture was degassed with argon for 5 min and then palladium acetate (7.34 mg, 0.033 mmol) was added to it. The reaction mixture was heated to 100° C. for 18 h. Then, it was filtered through diatomaceous earth (Celite®) and the filtrate was evaporated to afford tert-butyl (1-((7-fluoro-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate which was taken to next step without purification. LC/MS (ESI) m/e 472.2 [(M+H)+, calcd for C26H35FN3O4 472.2]; LC/MS retention time (method C): tR=2.17 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[C:13]3[N:14]([C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=4)[N:15]=[CH:16][C:12]=3[CH2:11][CH2:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.CC(OC([NH:64][CH:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=O)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH2:64][CH:65]1[CH2:70][CH2:69][N:68]([C:21]([C:20]2[CH:24]=[CH:25][C:17]([N:14]3[C:13]4[C:7]5[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=5[CH2:10][CH2:11][C:12]=4[CH:16]=[N:15]3)=[CH:18][CH:19]=2)=[O:22])[CH2:67][CH2:66]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccc(C(=O)O)cc1)CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccc(C(=O)N3CCC(N)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.3 g (0.85 mmol)) 4-(7-acetylamino-4,5-dihydro-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-benzoic acid (prepared analogously to Example 1), 0.32 g (1.00 mmol) TBTU and 0.75 ml (4.38 mmol) diisopropylethylamine in 25 ml dichloromethane is stirred for 15 minutes at ambient temperature and then combined with 0.17 g (0.86 mmol) 4-N-Boc-aminopiperidine. After 2.5 hours the reaction mixture is poured onto 25 ml 5% potassium carbonate solution. The organic phase is dried and evaporated down. The residue is triturated with ethyl acetate/ether.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:8])[CH2:6][CH3:7].Cl[CH2:10][C:11]1[CH:37]=[CH:36][C:14]([C:15]([NH:17][C:18]2[S:19][C:20]3[C:26]([CH:27]4[CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28]4)=[CH:25][CH:24]=[C:23]([O:34][CH3:35])[C:21]=3[N:22]=2)=[O:16])=[CH:13][CH:12]=1>O>[O:32]1[CH2:33][CH:27]([C:26]2[C:20]3[S:19][C:18]([NH:17][C:15](=[O:16])[C:14]4[CH:13]=[CH:12][C:11]([CH2:10][N:4]([CH3:3])[C:5](=[O:8])[CH2:6][CH3:7])=[CH:37][CH:36]=4)=[N:22][C:21]=3[C:23]([O:34][CH3:35])=[CH:24][CH:25]=2)[CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CCC(=O)NC
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)N(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(C4COCCOC4)c3s2)cc1
Temperature: 55 °C
Yield: 4 %

Procedure:
Sodium hydride (4.8 mg, 60% disp. in mineral oil, 0.2 mmol) was added to N-methylpropionamide (1 ml, 11 mmol), followed by 4-chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-benzamide (50 mg, 1.2 mmol) and the reaction mixture was heated to 55° C. for 3 hrs. After cooling, the mixture was diluted with water (5 ml) and extracted twice with ethyl acetate (5 ml). The combined organic phases were dried with magnesium sulfate, filtered and evaporated. Final purification with preparative HPLC and final dry-freezing afforded the title compound as white solid (23 mg, 42% yield). MS: m/e=484(M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH:9](O)[CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18].B(F)(F)F.CCOCC>O.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(c1ccccc1)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 30.7 %

Procedure:
A mixture of 5.0 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-phenylbenzo[b]thiophene, 10 ml of boron trifluoride etherate and 20 ml of glacial acid is refluxed for 1 hour. The mixture is cooled, diluted with water and basified with dil sodium hydroxide solution. Extraction with dichloromethane followed by column chromatography over silica (50% dichloromethane in hexane) gives 1.45 g of 6,7-dichloro-5-methoxy-2-phenylbenzo[b]thiophene, mp 144°-145°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](F)=[C:7]([CH:10]=1)[CH:8]=O)#[N:2].C(Cl)Cl.O.[NH2:16][NH2:17]>>[C:1]([C:3]1[CH:10]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:17][N:16]=[CH:8]2)#[N:2]
Reactant: NN
Reactant: N#Cc1ccc(F)c(C=O)c1
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2[nH]ncc2c1
Reaction time: 8 h

Procedure:
5-Cyano-2-fluorobenzaldehyde (512 mg, 3.43 mmol) was dissolved in hydrazine hydrate (25 mL) at room temperature and the solution left to stand overnight. To this reaction mixture was added methylene chloride (30 mL). The mixture was purified by filtration through a pad of silica eluting with methylene chloride, concentrated in vacuo to afford a white solid:
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13]([C:15]2O[C:17]([NH:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[N:18][N:19]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>ClCCl>[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:17]2[N:20]([CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C:15]([C:13]([NH:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:14])=[N:19][N:18]=2)[CH2:28]1
Reactant: OC1CCCNC1
Reactant: CC(C)=CCNc1nnc(C(=O)NCc2cccc3ccccc23)o1
Solvent: ClCCl
Product: CC(C)=CCn1c(C(=O)NCc2cccc3ccccc23)nnc1N1CCCC(O)C1
Temperature: 200 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.12 g 5-(3-methyl-but-2-enyl)amino-[1,3,4]oxadiazole-2-carboxylic acid-(naphth-1-ylmethyl)-amide and 1.80 g 3-hydroxypiperidine is stirred for 20 min at 200° C. in a microwave. After cooling to ambient temperature dichloromethane is added, the organic phase is washed once with water and once with 1 M hydrochloric acid, dried over sodium sulphate, and the solvent is removed.