Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[N:20]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.7 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (138 mg, 0.5 mmol), 1-(bromomethyl)naphthalene (166 mg, 0.75 mmol) and Na2CO3 (138 mg, 1 mmol) in DMF (10 mL) was stirred at 80° C. for 5 h. It was cooled to room temperature and poured into water (50 mL). It was extracted with EA (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 100% EA to afford the desired product as a black solid (143 mg, 69%); LC/MS: MS (ES+) m/e 417 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 3.42 (t, J=4.5 Hz, 4H), 3.67 (t, J=4.5 Hz, 4H), 3.93 (s, 3H), 5.92 (s, 2H), 6.70 (d, J=7.2 Hz, 1H), 7.09 (s, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.57-7.65 (m, 2H), 7.87 (d, J=9.0 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 8.34 (d, J=7.2 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN([C:14]([O:18][N:19]1N=NC2C=CC=N[C:20]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC.O>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:19]([O:18][CH3:14])[CH3:20])=[O:10])=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(O)cn1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a suspension of 5-hydroxypicolinic acid (1.0 eq), HATU (1.2 eq) and N-methoxymethanamine hydrochloride (1.2 eq) in dry DMF was added DIEtOAc (2.5 eq) dropwise at rt. The mixture was then stirred overnight at rt. After addition with water, the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (87% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:3]=2[CH3:2])[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: Cc1ccncc1-c1c[nH]c(=O)[nH]c1=O
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2cnccc2C)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Yield: 12.9 %

Procedure:
To a mixture of 5-(4-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep 11, 605 mg, 2.53 mmol) and K2CO3 (349 mg, 2.53 mmol) in DMF (10 ml), 3-bromo-1,1dimethoxy-propane (399 μl, 2.78 mmol) was added in two portions over 2 days and the mixture was contemporarily stirred at room temperature. Water was then added and washed with Et2O, the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-02) to give 100 mg of the title compound (27% yield).
Reaction SMILES: [O:1]=[C:2]([C:7]1[N:8]([C:12]2[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:16]=2[C:17]([O-:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)[C:3]([F:6])([F:5])[F:4].O.C(=O)([O-])[O-].[K+].[K+].SCC(CO)O>CN(C=O)C>[O:1]=[C:2]([C:7]1[N:8]([C:12]2[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:16]=2[C:17]([OH:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)[C:3]([F:4])([F:5])[F:6]
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: OCC(O)CS
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
4-[2-(1-Oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate (2.5 g) from Example 13 was dissolved in DMF (45 mL). Water (0.4 mL) followed by potassium carbonate (3.1 g) were added and the reaction mixture stirred at room temperature for 48 hours. Tlc of the reaction mixture showed the reaction to be incomplete. Additional potassium carbonate (0.6 g) and water (0.2 mL) were added and the reaction mixture stirred at room temperature for an another 18 hours. The insoluble materials were removed from the reaction mixture by filtration and washed with DMF. A 10% citric acid solution (100 mL) was added slowly to the filtrate and the resulting mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent removed under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to afford 2.06 g (85% yield) of the title compound, mp 185°-188° C., MS (FAB, thioglycerol) 550.3 (M+1).
Reaction SMILES: C(O)C.[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([F:17])[F:16])=[C:11](Cl)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([F:17])[F:16])=[C:11]([NH:26][CH2:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)n1ncc(Cl)c(C(F)F)c1=O
Reactant: NCc1ccncc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(C(F)F)c1=O

Procedure:
20 ml of an absolute ethanol solution of 0.71 g of 2-tert-butyl-5-chloro-4-difluoromethylpyridazin-3-(2H)-one, 0.33 g of 4-picolylamine and 0.33 g of triethylamine, was reacted for 5 hours under heating and refluxing and left to cool. Then, the mixture was extracted with ethyl acetate, then washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was subjected to column chromatography, and using an eluent (n-hexane:ethyl acetate=1:2), 0.32 g of the desired product (Compound No. 12) having a melting point of from 142° to 143° C. and 0.04 g of amorphous 2-tert-butyl-5-(4-pyridylmethylamino)-4-(4-pyridylmethyliminomethylidenyl)pyridazin-3-(2H)-one (Compound No. 2) as a by-product, were obtained.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[CH:36]=[C:37]([CH2:42][C:43]([OH:45])=[O:44])[CH:38]=[CH:39][C:40]=1[F:41]>>[F:41][C:40]1[C:35]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][C:15]=2[CH2:14][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[CH:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:39]=1
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1F

Procedure:
Prepared according to the procedure described in Example 7, Step 2, using the following starting materials: (4S,5R)-4-methyl-5-phenyl-3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-oxazolidin-2-one and 3-bromo-4-fluorophenylacetic acid. M+H is 488.
Reaction SMILES: BrC1C=CC=CC=1C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][CH:21]=1)[NH2:15].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([NH:43][C:44]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[C:12]([Cl:11])[CH:13]=1)=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccccc1Br
Agent: O=C(N=C=S)c1ccccc1Br
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Br)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 70%).
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]([N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>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.[Cu]I.CCN(CC)CC>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:20]=[CH:19][C:5]([N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1)([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCN(CCCCCC)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
4-Iodo-N,N-dihexylaniline (3.150 g, 8.13×10−3 mol), Pd(PPh3)2Cl2 (0.332 g, 4.73×10−4 mol), CuI (0.130 g, 6.83×10−4 mol) and Et3N (20 ml) were added to a 100-ml round-bottom flask. Ar was bubbled into the reaction mixture for 5 min before (trimethylsilyl)acetylene (2.40 ml, 1.70×10−2 mol) was added. The reaction mixture was stirred at 45° C. for 18 h under Ar. After the solvent was removed in vacuo, the residue was chromatographed on silica gel 4:1 hexane:CHCl3 as the eluent. Yield=2.861 g (98% based on 3.150 g of 4-iodo-N,N-dihexylaniline). 1H NMR (250 MHz, CDCl3): δ 7.29 (d, 2H, J=9.0 Hz, Ph), 6.50 (d, 2H, J=9.0 Hz, Ph), 3.24 (t, 4H, J=7.7 Hz, —NCH2—), 1.43-1.65 (m, 4H, —NCH2CH2—), 1.19-1.41 (m, 12H, —CH3—), 0.89 (t, 6H, J=6.5 Hz, —CH3), 0.22 (s, 9H, Si—CH3). CI MS m/z: 358.292 ((M+H)+) (calcd 358.293).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:12]#[N:13])[CH2:2]1.S(=O)(=O)(O)[OH:22]>O>[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C:12]([NH2:13])=[O:22])[CH2:2]1
Reactant: N#CC(=C1CSc2ccccc2N1)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)C(=C1CSc2ccccc2N1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 30 parts of (2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)acetonitrile, 180 parts concentrated sulfuric acid and 18 parts water is stirred at room temperature for 11/2 hours. The mixture is cooled to 0°-5° and diluted with 1 to 2 volumes of water which results in a crystalline solid which is filtered, dried and crystallized from methanol to afford crystalline 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-chlorophenyl)acetamide melting at about 188°-191°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.26) (0.300 g, 0.763 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.316 g, 0.839 mmol) according to the general procedure VI. Obtained as an off-white solid (0.040 g, 10%). MS (ISP) 532.1 [(M+H)+]; mp 227° C.
Reaction SMILES: C(O[C:4](=[O:14])[C:5](CC)(Br)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:15]([NH2:18])(=[S:17])[CH3:16]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[S:17][C:15]([CH3:16])=[N:18][C:4]=1[OH:14])=[O:7])[CH3:10]
Reactant: CCOC(=O)C(Br)(CC)C(=O)OCC
Reactant: CC(N)=S
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(C)nc1O
Yield: 28.9 %

Procedure:
A mixture of ethyl 2-bromo-propanedioic acid diethyl ester (32.0 g, 133.2 mmol) and thioacetamide (10.0 g, 133.2 mmol) in toluene (130 ml) is refluxed for 4 h and then cooled. The insoluble material is filtered off and the filtrate is concentrated. The residue is suspended in diisopropyl ether and collected by filtration to give the 4-hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (7.2 g, 38.5 mmol, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:38]4[CH:39]=[CH:40][C:35]([O:34][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:36][CH:37]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCc5ccccc5)cc4)ccc(F)c32)cc1
Yield: 83 %

Procedure:
(1S,2S)-2-[4-((R)-7-Fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 0.6 g, 1.7 mmol), 4-benzyloxyphenylboronic acid (1.53 g, 6.7 mmol), copper (II) acetate (306 mg, 1.7 mmol), triethylamine (1.83 mL, 13.1 mmol), 4-dimethylaminopyridine (21 mg, 0.17 mmol) and 4 Å molecular sieves (3 g) are suspended in dichloromethane and stirred under an oxygen atmosphere over a weekend. The mixture is filtered through a plug of CELITE filter aid, washing the filter cake with dichloromethane. The organic phases are washed with 1 M aqueous HCl solution, dried and the solvent removed. The residue is purified by flash chromatography (0-40% ethyl acetate in cyclohexane) to give the title compound (Yield 0.76 g). LC (METHOD 6): tR=1.04 min; Mass spectrum (ES+): m/z=539 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:28]=[CH:27][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:17]([C:21](Cl)=[O:22])=[N:16][CH:15]=[C:14]([O:24][CH3:25])[C:13]=3[C:12]2=[O:26])=[CH:8][CH:7]=1>O.CC(C)=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:17]([C:21]([N:1]=[N+:2]=[N-:3])=[O:22])=[N:16][CH:15]=[C:14]([O:24][CH3:25])[C:13]=3[C:12]2=[O:26])=[CH:27][CH:28]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cnc(C(=O)Cl)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cnc(C(=O)N=[N+]=[N-])c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.33 h

Procedure:
To a solution of sodium azide (0.24 g, 3.69 mmol) in water (2.5 mL) was added 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl chloride (1.17 g, 3.36 mmol) in acetone (15 mL). After 20 minutes, the product mixture was concentrated under vacuum to provide 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl azide. The crude azide (1.19 g, 3.35 mmol) in DMF (20 mL) was heated to 110° C. After 20 minutes, the product mixture was cooled for 10 minutes, then 1N NaOH (3.3 mL) was added. After 20 minutes, the mixture was concentrated under vacuum, re-dissolved in toluene and CHCl3 and evaporated. The residue was partitioned between CHCl3 and saturated sodium bicarbonate. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11]C)=O)[CH:5]=[N:6][C:7]=1I.[C:13]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>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>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:11])[CH:5]=[N:6][C:7]=1[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cnc(I)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncc(C=O)cc1Br
Temperature: 110 °C
Yield: 55.2 %

Procedure:
To a mixture of methyl 5-bromo-6-iodo-3-pyridinecarboxylate (232 mg, 0.679 mmol), tetrakis(triphenylphosphine)palladium (0) (39.2 mg, 0.034 mmol), and K2CO3 (281 mg, 2.036 mmol) in dioxane (5 ml), trimethylboroxin (0.095 ml, 0.679 mmol) was added under N2. The reaction mixture was heated at 110° C. and more tetrakis(triphenylphosphine)palladium (0) was added in several portions until starting material was not detected by HPLC. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude of reaction was purified by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc to afford the title compound (75 mg, 48%) as a yellow solid.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)CC1.[Li+].[CH3:25][CH2:26][CH2:27][CH2-:28].[CH2:29]1[O:39][C:32]2([CH2:37][CH2:36]C(=O)[CH2:34][CH2:33]2)[O:31][CH2:30]1>C1COCC1>[C:26]1(=[C:25]2[CH2:36][CH2:37][C:32]3([O:39][CH2:29][CH2:30][O:31]3)[CH2:33][CH2:34]2)[CH2:28][CH2:27]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [CH2-]CCC
Agent: [Br-]
Agent: [Li+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Solvent: C1CCOC1
Product: C1COC2(CCC(=C3CC3)CC2)O1
Temperature: -60 °C
Yield: 53.3 %

Procedure:
Cyclopropyltriphenylphosphonium bromide (10.8 g, 28 mmol) was suspended in dry THF (30 mL) and cooled to −60° C. N-Butyllithium (1.6M in THF, 17 mL, 27 mmol) was added dropwise at −40 to −60° C. The temperature was raised to 20° C. and after 3 hours at this temperature, the reaction mixture was cooled to −60° C. 1,4-Cyclohexane dione mono ethylene ketal (4.0 g, 26 mmol) dissolved in THF (30 mL) was added at −60° C. whereafter the temperature was raised to 20° C. After 16 hours the reaction mixture was diluted with THF (75 mL) filtered through hyflo and concentrated in vacuo. The residue was purified by flash chromatography (4×15 cm column of silica) using heptane and ethyl acetate (4:1) as eluent to give 2.5 g of 8-cyclopropylidene-1,4-dioxa-spiro[4.5]decane (cf Synthetic Communications 21(20), 2015-2023, 1991).
Reaction SMILES: C([N:3](CC)CC)C.ClC(OCC(C)C)=O.[S:16]1[CH:20]=[CH:19][C:18]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]4[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=[C:37]([C:45](O)=[O:46])[CH:36]=4)[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:17]1=2.N>C(#N)C.C(OCC)(=O)C>[S:16]1[CH:20]=[CH:19][C:18]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]4[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=[C:37]([C:45]([NH2:3])=[O:46])[CH:36]=4)[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:17]1=2
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.7 %

Procedure:
Triethylamine (0.25 ml, 1.8 mmol) and isobutyl chloroformate (0.19 ml, 1.4 mmol) were added to a solution (10 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxylic acid (0.53 g, 1.2 mmol) in acetonitrile with cooling in an ice-bath, followed by stirring at 0° C. for 3 hours. 28% Aqueous ammonia (0.15 ml) was added thereto and the reaction mixture was stirred at room temperature for 5 minutes. Ethyl acetate was further added thereto, then the reaction mixture was washed with water and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1), and concentrated under reduced pressure. The residue (0.2 g) was dissolved and recrystallized from the mixed solvent of ethyl acetate and isopropyl ether to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-quinolin-2-carboxamide (79 mg, yield: 16%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=S)=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH3:28]>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[NH:28])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1
Reactant: N
Product: COc1ccc(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.05 g, 0.00488 mol), N-[3-(4-methoxybenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.5 g, 0.0041 mol)and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 0.96 g (61.5%) m.p. 165°-166 ° C.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH2:4].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:28](Cl)=[O:29])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH:4][C:28]([C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:29]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: O=C(NCC(F)(F)C(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 2,2,3,3,3-pentafluoro-propylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.