Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[F:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: Cc1ccc(B(O)O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc(-c2ccc(C)cc2F)c1
Temperature: 80 °C
Reaction time: 42 h
Yield: 42.1 %

Procedure:
To a solution of methyl 2,6-dichloroisonicotinate (3.34 g, 16.2 mmol) in toluene (100 mL) were added (2-fluoro-4-methylphenyl)boronic acid (1.4 g, 9.09 mmol), (tetrakistriphenylphosphine)palladium (0) (0.94 g, 0.81 mmol) and sodium carbonate (2.0 M in water; 8.1 g, 16.2 mmol). The mixture was degassed with nitrogen (3×) and heated to 80° C. After 42 h, the mixture was cooled to ambient temperature and saturated NaHCO3 was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (1.07 g). MS 280.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][O:15][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
To an ice-cooled solution of 2.02 g (8.3 mmol) of 5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol and 1.73 ml (12.4 mmol) of Et3N in 100 ml of dichloromethane were added 0.67 ml (8.7 mmol) of methanesulfonyl chloride under stirring within 15 min keeping the temperature at 0-10° C. The reaction mixture was stirred at RT for 1 h 15 min. Water was added and after 5 min, the reaction was then partitioned between ether and water. The water was extracted again with ether (two times), the organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and concentrated to yield 2.50 g of the title compound as light brown oil.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([OH:30])=O)=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)[C:44]2[CH:45]=[CH:46]C=[CH:48][C:43]=2N=N1.[CH:57]([N:60](C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([NH:40][CH:44]5[CH2:43][CH2:48][N:60]([CH3:57])[CH2:46][CH2:45]5)=[O:30])=[C:21]5[C:25]=4[O:24][C:23]([CH3:26])([CH3:27])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylic acid 4f (931 mg, 2 mmol) was dissolved in 50 mL of dichloromethane followed by the addition of 1-methyl-piperidyl-4-yl-amine (228 mg, 2 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (642 mg, 2 mmol) and diisopropylethylamine (775 mg, 6 mmol). The reaction solution was stirred for 1.5 hours. The resulting mixture was added with 50 mL of saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with water (15 mL), saturated sodium chloride solution (15 mL) successively, dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-N-(1-methyl-4-piperidyl)-3H-benzofuran-4-carboxamide 4 (793 mg, yield: 70.8%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:30][CH2:31][CH3:32])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:29])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)=[CH:13][C:12]=1[N+:26]([O-:28])=[O:27])[CH3:2].[OH:33][C:34]1[C:48]([O:49][CH3:50])=[CH:47][C:37]2[C:38](=[O:46])[N:39]3[CH2:45][CH2:44][CH2:43][C@H:40]3[CH2:41][NH:42][C:36]=2[CH:35]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC(C)=O.O>[CH2:1]([O:3][CH:4]([S:30][CH2:31][CH3:32])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:29])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:33][C:34]2[C:48]([O:49][CH3:50])=[CH:47][C:37]3[C:38](=[O:46])[N:39]4[CH2:45][CH2:44][CH2:43][C@H:40]4[CH2:41][NH:42][C:36]=3[CH:35]=2)=[CH:13][C:12]=1[N+:26]([O-:28])=[O:27])[CH3:2]
Reactant: COc1cc2c(cc1O)NC[C@@H]1CCCN1C2=O
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCCBr)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]

Procedure:
A solution of (2S)-N-[4-(5-bromopentyloxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula I. (549 mg, 1 mmol), 8-hydroxy-7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one (248 mg, 1 mmol) II and K2CO3 (414 mg, 3 mmol) in dry acetone (20 mL) was refluxed for 48 h. After the completion of reaction as indicated by TLC, EtOAc, the reaction mixture was poured on to the water and then extracted with ethylacetate. Evaporation of the organic layer gave the crude product, which was further purified by column chromatography on silica gel eluting with EtOAc:hexane (8:2) gave the pure (2S)-N-{4-[5-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)pentyloxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:21]#[N:22])([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1>>[C:21]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)#[N:22]
Reactant: CNCCc1ccc(C(=O)OC)cc1
Reactant: CCOC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Product: CCOC(=O)C(C#N)(CCCN(C)CCc1ccc(C(=O)OC)cc1)c1ccc(OC)c(OC)c1

Procedure:
Reaction of 1c with 2b produced 3p. MS found M+H=483. The oxalate salt of 3p was recrystallized from ethyl acetate; mp 75-77° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:13])[C:8]=1[Si:9]([CH3:12])([CH3:11])[CH3:10])[NH2:5].[CH2:14]([N:17]([CH2:31][CH:32]=[CH2:33])[CH:18]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][CH:23]=1)[C:19](O)=[O:20])[CH:15]=[CH2:16].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH2:31]([N:17]([CH2:14][CH:15]=[CH2:16])[CH:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=1)[C:19]([NH:5][C:4]1[CH:6]=[C:7]([F:13])[C:8]([Si:9]([CH3:10])([CH3:12])[CH3:11])=[C:2]([F:1])[CH:3]=1)=[O:20])[CH:32]=[CH2:33]
Reactant: C[Si](C)(C)c1c(F)cc(N)cc1F
Reactant: C=CCN(CC=C)C(C(=O)O)c1ccc(COC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CCN(CC=C)C(C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1)c1ccc(COC)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (5 g, 24.84 mmol), 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (8.21 g, 29.81 mmol), DMAP (3.34 g, 27.32 mmol) and DIEA (21.69 mL, 124.20 mmol) in ethyl acetate (150 mL) was added T3P (29.2 mL, 49.68 mmol), and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give 2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide (6.79 g, 14.81 mmol, 59.6%) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:5]([O:4][CH2:2][CH3:3])=[O:11])=[S:28])=[CH:22][C:21]=1[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: CC(C)OC(=O)c1cc(N=C=S)ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCN1C(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
1.8 g (0.01 mol) of proline ethyl ester hydrochloride and 1.0 g of triethylamine were added dropwise to 30 ml of benzene and 2.6 g (0.01 mol) of 4-chloro-3-isopropoxycarbonylphenyl isothiocyanate were added thereto. The mixture was stirred at room temperature for an hour, washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by means of silica gel column chromatography to give 2.5 g (yield 63%) of the desired product as a yellow glassy substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.CCN(C(C)C)C(C)C.Cl.[NH:25]1[C@@H:34]2[C@@H:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([N:25]3[CH:34]4[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]4)[CH2:28][CH2:27][CH2:26]3)=[O:14])[CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: C1CC[C@@H]2NCCC[C@@H]2C1
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N2CCCC3CCCCC32)cs1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
5-(2-Methyl-2H-pyrazol-3-yl)-thiophene-3-carboxylic acid (0.084 g, 0.40 mmol) was dissolved in THF (2 mL) then DIPEA (0.22 mL, 1.3 mmol) and cis-decahydro-quinoline hydrochloride (DHQ [CIS-S]) (0.084 g, 0.48 mmol) were added followed by HATU (0.182 g, 0.48 mmol). The resulting mixture was stirred overnight then the mixture was diluted with water and extracted with DCM (×2). The organics were dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on a silica II cartridge, eluting with 50-100% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.101 g). LCMS m/z 330.19 [M+H]+ R.T.=10.43 min (Analytical Method 2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:42][CH2:41][C:36]4([CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:44]([O-:46])=[O:45])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-:47][C:48]#[N:49].[K+].O>CO>[NH2:49][C:48]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:43])[C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:34][CH2:35][C:36]4([CH2:37][CH2:38][CH2:39][CH2:40]4)[CH2:41][CH2:42]3)=[CH:31][CH:32]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:44]([O-:46])=[O:45])[CH2:7][S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:47]
Reactant: N#C[O-]
Reactant: NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)CC3)cc2)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)CC3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of Example 287 (60 mg, 0.1 mmol) and potassium cyanate (20 mg, 0.25 mmol) in methanol (1 mL) was stirred at 55° C. for 1.5 hours, cooled to room temperature, treated with water, and extracted with dichloromethane. The combined extracts were washed with saturated sodium bicarbonate, dried (MgSO4), filtered, and concentrated. The concentrate was purified by reverse phase HPLC with 0-100% acetonitrile/water containing 0.1% TFA to provide the desired product. MS (ESI(+)) m/e 709 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ11.97 (s, 1H), 8.53 (d, 1H), 8.32 (d, 1H), 7.85 (dd, 1H), 7.73 (d, 2H), 7.25-7.10 (m, 6H), 6.93 (d, 2H), 5.90 (s, 1H), 4.10 (m, 1H), 3.34 (m, 6H), 2.91 (t, 2H), 1.75 (m, 2H), 1.59 (m, 4H), 1.42 (m, 8H), 1.34 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:14][CH:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:16]([O:18]CC1C=CC=CC=1)=[O:17])([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][P:4]([CH2:14][CH:15]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:16]([OH:18])=[O:17])([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)OCc1ccccc1)CN1C(=O)CNC1=O
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)CNC1=O
Reaction time: 1 h

Procedure:
0.27 g 0.64 mmol) of benzyl 2(RS)-[[(RS)-(ethoxy)[(2,5-dioxo-1-imidazolidinyl)methyl]phosphinyl]methyl]-4-methylvalerate was dissolved in 10 ml of ethanol and the solution was hydrogenated in the presence of 0.2 g of 10% palladium/carbon at room temperature and under atmospheric pressure. After 1 hours, the catalyst was removed by filtration and the solvent was evaporated to give 0.22 g of 2(RS)-[[(RS)-(ethoxy)[(2,5-dioxo-1-imidazolidinyl)-methyl]phosphinyl]methyl]-4-methylvaleric acid in the form of a foam;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)/[C:10](=[CH:13]/[N:14](C)C)/[CH2:9][CH2:8][O:7][C:6]=2[CH:17]=1.Cl.Cl.[NH2:20]N>C(O)(C)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[C:10]([CH2:9][CH2:8][O:7][C:6]=2[CH:17]=1)=[CH:13][NH:14][N:20]=3
Reactant: NN
Reactant: CN(C)/C=C1\CCOc2cc(Br)ccc2C1=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Brc1ccc2c(c1)OCCc1c[nH]nc1-2
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a suspension of 8-bromo-4-[1-dimethylamino-meth-(E)-ylidene]-3,4-dihydro-2H-benzo[b]-oxepin-5-one (5.32 g, 17.9 mmol) in isopropyl alcohol (50 mL) was added powdered hydrazine dihydrochloride (3.77 g, 35.9 mmol) at room temperature, then the mixture stirred for 2 h. The reaction mixture was diluted with water (20 mL) and then heated at 100° C. for 2 h before cooling to room temperature. The reaction mixture was concentrated in vacuo to remove the volatile solvent. The resulting suspension was filtered and the filtrate washed with water and dried under vacuum at 40° C. to yield 8-Bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene as a pale yellow solid (4.28 g, 90%). 1H NMR δ (ppm)(DMSO-d): 8.07 (1 H, d, J=8.52 Hz), 7.64 (1 H, s), 7.30-7.24 (1 H, m), 7.21 (1 H, d, J=2.07 Hz), 4.24 (2 H, dd, J=5.63, 4.50 Hz), 3.00 (2 H, t, J=5.09 Hz).
Reaction SMILES: Br[C:2]1[N:3]([CH2:13][C:14]2[S:18][C:17]([CH2:19][CH3:20])=[CH:16][CH:15]=2)[C:4]2[N:5]=[C:6]([NH2:12])[NH:7][C:8](=[O:11])[C:9]=2[N:10]=1.[NH2:21]N.COCCO>O>[NH2:21][C:2]1[N:3]([CH2:13][C:14]2[S:18][C:17]([CH2:19][CH3:20])=[CH:16][CH:15]=2)[C:4]2[N:5]=[C:6]([NH2:12])[NH:7][C:8](=[O:11])[C:9]=2[N:10]=1
Reactant: NN
Reactant: CCc1ccc(Cn2c(Br)nc3c(=O)[nH]c(N)nc32)s1
Solvent: COCCO
Solvent: O
Product: CCc1ccc(Cn2c(N)nc3c(=O)[nH]c(N)nc32)s1
Reaction time: 48 h

Procedure:
A mixture of 8-bromo-9-(5-ethyl-2-thenyl)guanine (6.5 g; 18.3 mmol) and 60% aqueous hydrazine (200 ml) was heated to reflux under nitrogen atmosphere for 20 hours. 2-Methoxyethanol (50 ml) was added and the refluxing continued for an additional 48 hours in the open air. The orange-brown solution was cooled, diluted with water (150 ml) and allowed to crystallize in the refrigerator overnight. The crude product thus obtained was converted to the hydrochloride salt by recrystallizing from boiling isopropanol and 1N HCl. Yield, 0.49 g; mp 215°-218° C., dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=3)[C:9]=2[CH2:20][C:21]2[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:46].C(O)(C)C>C(Cl)Cl>[ClH:46].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH2:20][C:21]3[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]3)[CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: Cl
Product: Oc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1
Reaction time: 2 h
Yield: 57 %

Procedure:
Charge a flask with 1-(2-{4-[2-(3-fluorophenyl)-6-methoxy-naphthalen-1-ylmethyl]-phenoxy}-ethyl)-piperidine (1.1 g, 2.3 mmol) dissolved in 250 mL methylene chloride and chill in ice. Add 6.0 mL of neat boron tribromide in portions with stirring and stir the reaction in ice for one hour then at room temperature for 2 hours. Pour the reaction into a two-phase mixture consisting of saturated sodium bicarbonate and an organic phase of 3/1 chloroform/isopropanol. Extract the compound into the organic phase using a separatory funnel, separate the phases and dry the organic layer over 3 Å molecular sieves. Evaporate and purify on a silica column eluting with 3% methanol/methylene chloride. Convert to the hydrochloride salt and lyophilize to yield 650 mg (57%) of the title compound: 1H-NMR (data reported for the free base) (CDCl3, 400 MHz) δ 7.73 (d, J=9.6 Hz, 1H); 7.61 (d, J=8.0 Hz, 1H); 7.32-7.30 (m, 1H); 7.28-7.24 (m, H); 7.15 (d, J=2.0 Hz, 1H); 7.04-6.94 (m, 4H); 6.79 (d, J=8.4 Hz, 2H); 6.62-6.59 (m, 2H); 4.28 (s, 2H); 4.13 (t, J=5.6 Hz, 2H); 2.92-2.92 (m, 2H); 2.72-2.64 (m, 4H); 1.74 (d, J=4.8 Hz, 4H); 1.51-1.51 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[Cl:26][CH:27]([CH3:31])[C:28](Cl)=[O:29]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:26][CH:27]([CH3:31])[C:28]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23])=[O:29]
Reactant: CC(Cl)C(=O)Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(Cl)C(=O)Nc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
To a mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole (8.0 g, 19.0 mmol) in toluene was added 2-chloropropionyl chloride (3.62 g, 28.5 mmol), then zinc chloride (0.77 g, 5.7 mmol). The mixture was heated at reflux for 16 hours. After extractive workup and recrystallisation with heptane-ethyl acetate (1:1) the title product was obtained (7.02 g), 19F-NMR: −43.7; −64.2 ppm.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([Cl:36])(=[O:35])=[O:34])(=[O:26])=[O:25]>>[ClH:36].[N:11]1([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[S:24]([CH3:23])(=[O:26])=[O:25])(=[O:35])=[O:34])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)n1ccc2c(N3CCNCC3)cccc21
Product: Cl

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and 2-methylsulfonyl-phenylsulfonyl chloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.22 (br, 1H), 8.29 (d, J=8 Hz, 1H), 7.99 (t, J=8 Hz, 1H), 7.90-7.80 (m, 2H), 7.43 (d, J=8 Hz, 1H), 7.30-7.15 (m, 2H), 7.04 (d, J=3 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 3.56 (s, 3H), 3.29 (m, 8H); MS (ESI+) for m/z 420 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=3)=[N:7][C:6]=2[CH:19]=1.[C:20]([O-:23])([O-])=O.[K+].[K+].Br[CH2:27]CCBr>CC#N>[CH3:20][O:23][C:11]1[C:12]([O:18][CH3:27])=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:19][C:6]=2[N:7]=1
Reactant: BrCCCBr
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc3cc(F)ccc3s2)cc1O
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2nc3cc(F)ccc3s2)c(OC)c1OC
Temperature: 80 °C

Procedure:
To a solution of 5-fluoro-2-(3-hydroxy-4-methoxyphenyl)benzothiazole 5 (0.15 g, 0.55 mmol) in CH3CN (30 ml) were added K2CO3 (0.11 g, 0.82 mmol) and 1,3-dibromopropane (0.28 ml, 2.74 mmol), and the mixture was heated under reflux at 80° C. for 24 hours. The reaction mixture was allowed to cool at room temperature and then concentrated in vacuum. The residue was taken up with CHCl3 (30 ml), and the CHCl3 layer was washed with 0.2N NaOH aq (30 ml×2), then dried and concentrated in vacuum. The residue was purified by column chromatography on silica gel (chloroform), followed by recrystallisation from ethanol/water to give a white solid.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.[OH-].[Na+]>COCCOC.CCOC(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>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=3)=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)=[CH:21][CH:20]=1
Reactant: Cc1cccc(-c2nn3ccccc3c2Br)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccc(F)cc2)n1
Yield: 60.1 %

Procedure:
A solution of 3-bromo-2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridine (0.25 g, 0.9 mmol) and p-fluorophenyl-boronic acid (0.15 g, 1.04 mmol), in DME (10 mL) is purged with argon. The solution is treated with NaOH (0.07 g, 1.7 mmol) and (PPh3)4Pd (0.05 g, 0.04 mmol) then heated at reflux overnight. The reaction is then cooled, diluted in EtOAc, and washed with water and brine. The organic solution is dried over MgSO4 and the solvent removed in vacuo. The residue is purified by silica gel column chromatography using a mixture of hexanes/EtOAc to afford 0.164 g (62%) of desired product as a white solid. UV (95% EtOH) λmax 248 nm (ε 20386). TOF MS ES+ exact mass calculated for C19H14FN3 (p+1): m/z=304.1250. Found: 304.1249. Anal. Calcd for C19H14FN3: C, 75.23; H, 4.65; N, 13.85. Found: C, 75.10; H, 4.76; N, 13.70.