Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.N(CCO)CCO>C1COCC1>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: OC(CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 209.3 %

Procedure:
2-Chloroacetophenone (3 g., 19.4 mmol) was treated with (−) DIP-chloride (6.7 g., 20.9 mmol) in anhydrous THF (20 mL) at dry-ice bath temperature and left overnight. The temperature was raised to room temperature and THF was removed in vacuo. The residue was dissolved in ether (100 mL). The diethanolamine (4.58 g., 42.6 mmol) was added and the mixture stirred at room temperature for 5 hrs. The separated solid was filtered and the filtered cake was washed with hexane (40 mL) and ether (30 mL). The combined filtrates were evaporated to dryness to give 6.36 g of crude product. This was purified by silica gel column chromatography using 1% ether and petroleum ether 1.71 g (56%) of the desired product was obtained as an oil.
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=1)[N:9]([CH2:21][CH3:22])[CH:8]=[C:7]([C:23]([OH:25])=[O:24])[C:6]2=[O:26].[N:27]([O-])=O.[Na+].[F:31][P-:32]([F:37])([F:36])([F:35])([F:34])[F:33].[H+]>Cl.O>[F:31][P-:32]([F:37])([F:36])([F:35])([F:34])[F:33].[C:23]([C:7]1[C:6](=[O:26])[C:5]2[C:10](=[CH:11][C:12]([C:13]3[CH:14]=[C:15]([CH3:20])[N:16]=[C:17]([CH3:19])[CH:18]=3)=[C:3]([N+:2]#[N:27])[CH:4]=2)[N:9]([CH2:21][CH3:22])[CH:8]=1)([OH:25])=[O:24]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(N)c(-c3cc(C)nc(C)c3)cc21
Reactant: O=N[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [H+]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc([N+]#N)c(-c3cc(C)nc(C)c3)cc21
Reaction time: 0.12 h
Yield: 78 %

Procedure:
A 20 g portion of 6-amino-1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid monohydrate was suspended in 100 ml of 6 N HCl and placed in an ice/salt bath. When the temperature of the mixture had reached -10° C., a cold solution of 4.5 g of NaNO2 in 20 ml of H2O was added in portions over a period of a few minutes. The reaction mixture was stirred for 5-10 minutes during which time it became a clear solution. Hexafluorophosphoric acid (18 ml) was carefully added in one portion whereupon a precipitate separated immediately, the temperature rising to 0° C. before dropping again. The reaction mixture was stirred for 30 minutes after addition; and, then the precipitate was collected and washed successively with water, a small volume of cold ethanol, and finally with ether. The product was vacuum-dried at 50° C. for 48 hours in the presence of P2O5 to give 29.7 g (78%) of 3-carboxy-1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pvridinyl)-4oxo-6-quinolinyldiazonium hexafluorophosphate as its hydrohexafluorophosphate, m.p. 200°-205° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].CS(O[C@H:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])(=O)=O>[Cl-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][C@@H:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)[C@@H](C)OS(C)(=O)=O
Reactant: Nc1ccc(F)c(F)c1F
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F

Procedure:
In accordance with the process of Example 2, a condensation reaction was performed by using 2,3,4-trifluoroaniline (100 mg), potassium carbonate (188 mg), methyl (2R)-2-[(methanesulfonyl)oxy]propionate (78 mg) and tetrahexylammonium chloride (40 mg) to give the title compound as an oily substance. As the result of the analysis by reversed phase HPLC with the use of the compound of Example 1 as a specimen, the product corresponded to 38 mg (24%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)/[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.COC1C=C(C=C(C2C=CC(O)=CC=2)C(O)=O)C=C(OC)C=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C.Cl>C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5](/[CH:11]=[C:12](/[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)\[C:13]([OH:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(/C=C(/C(=O)O)c2ccc(O)cc2)cc(OC)c1
Agent: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(/C=C(\C(=O)O)c2ccc(O)cc2)cc(OC)c1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
E-3-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid, 7 (10.0 g, 33.3 mmol) was dissolved in a mixture of acetic anhydride (40 mL, 0.42 mole) and triethylamine (40 mL, 0.29 mole) and heated at 125° C. for 24 h. The mixture was cooled to room temperature. Ethyl acetate (150 mL) was added, further cooled to 5° C., acidified with concentrated HCl (30 mL) and stirred at this temperature for 90 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (2×50 mL) and extracted with aqueous NaOH (5M, 3×70 mL). The aqueous alkaline layer was acidified with glacial acetic acid (65 mL) to pH 5.2 and stirred at 0° C. for 30 min. Solid that separated was filtered and mother liquor was acidified with concentrated HCl (90 mL) and stirred at 5° C. for 1 h. Solid that separated was filtered, washed with cold water (2×50 mL) and dried at 45° C. for 6 h to yield, 19, (1.3 g, 13%): mp 135-137° C.; 1HNMR (400 MHz, DMSO-d6) δ 13.28 (br, 1H), 9.70 (br, 1H), 7.32 (d, J=10.4 Hz, 2H), 6.81(s, 1H, overlapped), 6.79 (d, J=9.7 Hz, 2H), 6.67 (d, J=2.5 Hz, 2H), 6.64 (t, J=2.5 Hz, 1H), and 3.73 (s, 6H); MS (EI) m/z 299[M]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.Cl[Sn]Cl.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Yield: 99.8 %

Procedure:
A solution of 2-(4-fluorophenyl)6-phenylmethoxy-1-{4-nitrobenzyl}-1,2,3,4-tetrahydroisoquinoline (3 g, 6.4 mmol) and SnCl2.H2O (7.2 g, 32 mmol) in DMF was stirred at room temperature overnight. The solvent was removed and the residue was treated with ethyl acetate (200 ml) and water (200 ml). The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (2.8 g, 100% yield): ES-MS (m/z) 439 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[OH:25][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(C(F)(F)F)cc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(C(F)(F)F)cc3)sc2c1O
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 7-hydroxy-2-(4-trifluoromethyl-phenyl)-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (40 mg, 0.11 mmol) and glycine (162 mg, 2.16 mmol) in 0.5 M sodium methoxide/methanol (4.1 mL) was refluxed for four days before it was cooled to room temperature and concentrated in vacuo. Water (20 mL) and 1N HCl (1.5 mL) was added and the mixture was extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (1.5 mL). The suspension was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (34 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.48 (br s, 1H), 8.94 (s, 1H), 8.35 (d, 2H), 7.96 (d, 2H), 4.03 (d, J=5.8 Hz, 2H); MS: (+) m/z 329.9 (M+1)
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.[BH3-]C#N.[Na+]>>[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH2:50][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:47]=[N:48][CH:49]=2)[O:38]1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: C1COCCN1
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC1(C)OB(c2cncc(CN3CCOCC3)c2)OC1(C)C
Yield: 71.4 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), morpholine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 28 mg of crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine. The crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 15.8 mg of the title compound (43%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:20]([NH:25][C:26](=O)[O:27]C1C=CC=CC=1)[CH2:21][CH2:22][CH2:23][CH3:24]>CN(C)C=O>[CH2:20]([NH:25][C:26]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:27])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: CCCCCNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (5.0 g, 22 mmol, CAS No. 417722-11-3) which was described in WO 02/32872 was dissolved in N,N-dimethylformamide (60 ml); sodium hydride (1.06 g, 27 mmol) was added thereto at room temperature; and the reaction mixture was stirred for 30 minutes. Phenyl N-n-pentylcarbamate (5.06 g, 24 mmol) while stirring at room temperature; and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate (insoluble portions were perfectly dissolved by adding a small amount of methanol); and the organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH; hexane:ethyl acetate=1:1, ethyl acetate, ethyl acetate:methanol=95:5 in this order). The obtained crystals were suspended in hexane:ethanol=10:1, filtered off, washed with hexane, and dried under aeration to yield the title compound as colorless crystals (1.55 g, 4.58 mmol, 21%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][C:12]1[CH:13]2[CH2:18][CH:15]([CH2:16][CH:17]=1)[C:14]2([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][C:12]2[CH:13]3[CH2:18][CH:15]([CH2:16][CH:17]=2)[C:14]3([CH3:19])[CH3:20])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC1(C)C2CC=C(CCBr)C1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C2CC=C(CCOc3ccc(I)cc3)C1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
A mixture of 4-iodophenol (0.4 g; 1.82 mmol), 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene (0.45 g, 1.97 mmol) and K2CO3 (0.3 g, 2.17 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature. Another portion of 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene (0.3 g) was added and stirring was continued for 6 h. The mixture was diluted to 50 ml with EtOAc and washed with H2O (50 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2) to give the title product (0.189 g; 28%), as pale paste. 1H-NMR (CDCl3) 0.81 (s, 3H); 1.26 (s, 3H); 2.06-2.44 (m, 8H); 3.91 (tr, 2H, J=6.97 Hz); 5.32 (s, 1H); 6.64 (d, 2H, J=8.96 Hz); 7.51 (d, 2H, J=8.96 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C(CO)=CC=CC=1>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1
Reactant: OB(O)c1ccco1
Reactant: Brc1cn(-c2ccccc2)cn1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-n2cnc(-c3ccco3)c2)cc1
Temperature: 80 °C
Yield: 21.1 %

Procedure:
4-Bromo-1-phenyl-1H-imidazole (200 mg, 0.9 mmol), furan-2-ylboronic acid (342 mg, 3 mmol), PEPPSI-iPr (18 mg, 0.026 mmol), and K2CO3 (640 mg, 4.64 mmol) were then combined in toluene-methanol (1:1) (4 ml). The reaction mixture was heated under microwave at 80° C. for 20 minutes. It was then filtered and washed with toluene-MeOH (5 ml), and the filtrate was concentrated to yield a crude mixture. The crude mixture was then column purified using 15-20% ethyl acetate/hexanes to afford the desired 4-(furan-2-yl)-1-phenyl-1H-imidazole (50 mg, 0.19 mmol, yield 21.4%) as a brown sticky liquid with an HPLC purity of 95.5%. LC-MS [M+H] 211 (C13H10N2O+H expected 211.08). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:5]([N+:15]([O-])=O)[CH:4]=1.Cl.[OH-].[Na+]>C(O)C>[NH2:15][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(-c2ccccn2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccccn2)c(N)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
1.63 g of 2-(4-methoxy-2-nitrophenyl)pyridine was dissolved in 14 ml of ethanol, and 8 g of stannous chloride dihydrate and 5.7 ml of concentrated hydrochloric acid were added. The mixture was stirred at a bath temperature of 100° C. for 3 hours. After cooling, the reaction mixture was made alkaline with a 50% aqueous solution of sodium hydroxide and extracted with benzene. The solvent was evaporated. The resulting dark brown oil was subjected to silica gel column chromatography and the column was eluted with chloroform. As a yellow oil, 967 mg (yield 68.2%) of 2-(2-amino-4-methoxyphenyl)pyridine was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[Cl:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][CH3:20])=[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:14]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([N:19]([C:16]1[CH:17]=[N:18][C:13]([Cl:12])=[CH:14][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH3:20])=[O:6]
Reactant: CNc1cnc(Cl)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
3,5-Dichlorobenzoyl chloride (635 mg, 3.03 mmol, CAS RN 2905-62-6) was added to a solution of 6-chloro-N-methyl-4-o-tolylpyridin-3-amine (470 mg, 2.02 mmol, prepared as described in WO2005/002577) and DIPEA (705 μL, 4.04 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred for 1 h after which the reaction mixture was loaded directly onto a silica gel column. The title compound was isolated by flash chromatography (25% EtOAc in n-hexane) as a foamy oil (641 mg, 78%). MS (ESI): m/z=404.9 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)([OH:3])=[O:2].[N-:12]=[N+:13]=[N-:14].[Na+].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCn1nnnc1S

Procedure:
Reaction of methyl 3-carboxypropyldithiocarbamate with sodium azide and sodium hydroxide as described in Example 7 gave 1-(3-carboxypropyl)tetrazole-5-thiol, m.p. 99°-101°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.Cl>O.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: COC(=O)CCS
Reactant: CC1OC1(Cn1cncn1)c1ccc(F)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A methanol (2.0 ml) solution containing (2RS,3RS)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.05 g), methyl 3-mercaptopropionate (0.11 ml) and a 28% sodium methylate-methanol solution (0.14 ml) was refluxed for 1.0 hour. The reaction mixture was cooled, to which was added water (10 ml). The mixture was neutralized with 1N aqueous solution of hydrochloric acid, followed by extraction with methylene chloride (5.0 ml×twice). The extract solution was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was subjected to a silica gel chromatography (2.5 cm×5 cm), followed by elution with ethyl acetate-hexane (1:2). The object fraction was concentrated, to which was added ethyl acetate to give (2RS,3RS)-2-(2,4-difluorophenyl)-3-mercapto-1-[(1H)-1,2,4-triazol-1-yl]-2-butanol (0.030 g) as colorless needles.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:10])#[N:2].S(=O)(=O)(O)[OH:30].[OH-].[NH4+]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([C:4]2[C:3]([C:1]([NH2:2])=[O:30])=[C:7]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:10])[S:6][N:5]=2)=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCCC1
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCCC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
1-[4-cyano-3-(4-nitrophenyl)isothiazol-5-yl]-3-(3-pyrrolidin-1-ylpropyl)urea (36.0 g) was added portion wise to concentrated sulfuric acid (180.0 mL) at ambient temperature over 20 min. The resulting suspension was heated to 45° C. over 90 min. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured into ice water (2000 ml), stirred for 30 min. The resulting mixture was made basic using ammonium hydroxide, filtered the solid and washed with water then dried in vacuo to give the title compound as off white solid (34.0 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A 3-L, 3-necked, round-bottomed flask under a positive pressure of nitrogen was equipped with a mechanical stirrer and charged with tert-butylhomopiperazine-1-carboxylate (1-BOC-homopiperazine) (73.0 g, 365.0 mmol) and anhydrous dichloroethane (800 mL). To this stirred solution was added cyclobutanone (25.5 g, 363.8 mmol). The pale yellow reaction was stirred at rt for 1 h, following which, sodium triacetoxyborohydride (92.5 g, 436.3 mmol) was added portion-wise over 1 h. The reaction mixture was stirred for 48 h. 1 N NaOH(aq) (225 mL) was added to the reaction mixture and stirred for 1 h. The phases were separated and the aqueous layer was extracted with dichloroethane (2×100 mL). The organic layers were pooled, washed with satd. aq. NaCl (1×250 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed by rotary evaporation under reduced pressure to afford the crude product as pale yellow semi-solid (92.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ ppm: 3.59-3.40 (m, 4H), 2.98-2.84 (m, 1H), 2.59-2.43 (m, 4H), 2.12-2.03 (m, 2H), 2.00-1.83 (m, 4H), 1.76-1.55 (m, 2H), 1.51-1.41 (s, 9H). MS m/z (ESI+): 255.2 (M+H+).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:77]([C:76]3[CH:75]=[CH:74][C:73]([N:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)=[CH:80][CH:79]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1N1CCN(Cc2cncnc2)CC1
Reaction time: 6 h
Yield: 29.3 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-morpholin-4-yl-benzaldehyde (1.1 eq, 0.052 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (8 mg, 30%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.24 (t, J=4.7 Hz, 4H, morpholine N(CH2)2), 3.62-3.65 (m, 6H, piperazine N(CH2)2 & CH2), 3.76 (t, J=4.8 Hz, 4H, morpholine O(CH2)2), 7.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 8.04 (d, J=8.9 Hz, 2H, phenyl H-2 & H-6), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2), 13.23 (s, br, 1H, imidazo[4,5-b]pyridine NH);