Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:35]C(O)=O)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C(Cl)Cl>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:34]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=2)=[CH:35][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:44][CH:43]=1
Reactant: O=CN1CCNCC1
Reactant: COc1ccc(C(=CC(=O)O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=CC(=O)N2CCNCC2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.41 ml of diphenylphosphoryl azide and 1.09 ml of 1-formylpiperazine were added to a 60 ml of a methylene chloride solution of 3.00 g of 3,3-bis(4-methoxyphenyl)acrylic acid and 2.94 ml of triethylamine. The reaction mixture was then stirred for 2 hours at room temperature, after which it was poured into a saturated aqueous solution of sodium bicarbonate and extracted twice with methylene chloride. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 80 ml of methanol, and 40 ml of a 10% w/v aqueous solution of sodium hydroxide were added to the resulting solution. The reaction mixture was stirred for 18 hours at room temperature and then poured into water; it was then extracted twice with methylene chloride. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography through 80 g of silica gel eluted with mixtures of methylene chloride and methanol ranging from 19:1 to 4:1 by volume to give 3.00 g of 1-[3,3-bis(4-methoxyphenyl)acryloyl]piperazine as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[C:8](Br)=[N:7][CH:6]=1)[CH3:2].[CH2:14]([Mg]Br)[CH3:15].O.C(OCC)(=O)C>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:9]1[C:8]([CH2:14][CH3:15])=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:13]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1cnc(Br)c(Br)c1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(CC)c(Br)c1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
Method-1: To a 0° C. cooled solution of ethyl-5,6-dibromonicotinate (1.0 g, 3.24 mmol, 1.0 eq., prepared by following the procedure described in WO2011024004) in THF (10 mL) was added [1,3-bis(diphenylphosphino)propane]dichloronickel (II) (351 mg, 0.65 mmol, 0.2 eq) and the solution was stirred for 5 min. Ethyl magnesium bromide (1M in THF, 3.88 mL, 3.88 mmol, 1.2 eq) was then added drop-wise to the above mixture at 0° C. The resulting mixture was continued to stir at the same temperature for 3 h. Water (10 mL) was then added to the above mixture, followed by ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was evaporated and the crude residue was purified by flash column chromatography (silica gel, diethyl ether-hexane system as eluent) to afford 500 mg (60%) of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.06 (d, J=1.5 Hz, 1H), 8.40 (d, J=1.5 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.05 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H); GC-MS (m/z) 257, 259 [M+, Br79, 81].
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[C:14]([S:16][CH3:17])[CH:13]=[C:12]([F:18])[CH:11]=1.IC.[Cl-].[Na+]>C1COCC1.C(C1C=CC=CC=1)C>[Br:9][C:10]1[CH:15]=[C:14]([S:16][CH3:17])[CH:13]=[C:12]([F:18])[C:11]=1[CH3:1]
Reactant: CSc1cc(F)cc(Br)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CI
Product: CSc1cc(F)c(C)c(Br)c1
Temperature: -73 °C
Reaction time: 1.5 h

Procedure:
7.5 ml of a 2 M solution of lithium diisopropylamide in THF/HEP/ethylbenzene (Aldrich) were dissolved in 30 ml of anhydrous THF and cooled to −73° C. A solution of 3.0 g of 1-bromo-3-fluoro-5-methylsulfanylbenzene in 10 ml of anhydrous THF added at a temperature between −73° C. and −67° C. Stirring was continued for 90 min at −75° C., then 1.0 ml of iodomethane was added at this temperature. The mixture was then warmed up to room temperature, 100 ml of a saturated aqueous solution of sodium chloride were added and the mixture was extracted twice with 100 ml each of EA. The extracts were dried and concentrated in vacuo to yield 2.0 g of the title compound as a slight yellow oil that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].CN(C)C=O.[CH2:30](I)[CH3:31]>O>[CH2:30]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[CH3:31]
Reactant: CCI
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)C4CC4)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)C1CC1)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 8 h

Procedure:
A mixture 1.57 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]cyclopropanecarboxamide, 0.36 g of sodium hydride (50% in oil) and 200 ml of dry dimethylformamide under argon was stirred at room temperature for 1 hour and then 0.60 ml of ethyl iodide was added. After stirring overnight, the mixture was poured into 200 ml of water and extracted with dichloromethane. The combined extracts were dried, the solvent removed and the residue chromatographed on a silica gel column with dichlormethane-methanol (97:3) as solvent. The fractions containing product were combined, the solvent removed and the solid recrystallized from dichloromethane-hexane to give 0.80 g of pale yellow crystals, mp 149°-151° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([C:10]([F:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]([CH3:20])[C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]=1[CH3:38])#[N:28]>O1CCCC1.CN(C)C1C=CN=CC=1.O>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:5][C:4]2[C:6]([CH3:20])=[CH:7][C:8]([C:10]([F:19])([C:11]([F:14])([F:13])[F:12])[C:15]([F:16])([F:17])[F:18])=[CH:9][C:3]=2[CH2:1][CH3:2])=[O:34])=[CH:31][C:30]=1[CH3:38])#[N:28]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: Cc1cc(C(=O)Cl)ccc1C#N
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(C)c1
Temperature: 50 °C
Yield: 84.5 %

Procedure:
2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylaniline (1.7 g) and pyridine (0.88 g) were dissolved in tetrahydrofuran (30 ml). To the solution, the crude product of 4-cyano-3-methylbenzoyl chloride (1.0 g) and 4-dimethylaminopyridine (0.03 g) were added and the mixture was stirred under heating at 50° C. for 2 hours. After adjusting to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was washed with a mixed solvent of hexane and ethyl acetate (ethyl acetate 10%) to obtain 4-cyano-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-3-methylbenzamide (2.1 g, yield 83%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[C:11]1([CH:17]2[C:23](=O)[NH:22][C:21]3=[C:25]4[C:30](=[N:31][C:32]5=[CH:33][CH:34]=[CH:35][C:19](=[C:20]35)[O:18]2)[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCCC1>[C:11]1([CH:17]2[CH2:23][NH:22][C:21]3=[C:25]4[C:30](=[N:31][C:32]5=[CH:33][CH:34]=[CH:35][C:19](=[C:20]35)[O:18]2)[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1Nc2c3c(nc4cccc(c24)OC1c1ccccc1)CCCC3
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc(C2CNc3c4c(nc5cccc(c35)O2)CCCC4)cc1
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
A solution of lithium aluminum hydride in tetrahydrofuran (1M, 12.0 ml) was added to dry tetrahydrofuran (30 ml) followed by aluminum chloride (1.60 g). The mixture was stirred for 15 mins and 1,3,9,10,11,12-hexahydro-3-phenyl-2H-quino[4,3,2-ef][1,4]benzoxazepine-2-one (3.30 g) was added, with stirring. After 30 mins, 10% sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (5% triethylamine-ethyl acetate). Evaporation of the appropriate fractions followed by recrystallization of the residue from dichloromethane-pentane gave 2.14 g (67.72%) of product, mp 194°-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.Cl[C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:19]=[C:18]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[C:29]2[CH:37]([F:39])[F:38])[N:17]=1>C1COCC1.C(O)(=O)C.O>[F:39][CH:37]([F:38])[C:29]1[N:28]([C:18]2[N:19]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:21]=[C:16]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[O:8][CH3:9])[N:17]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1ccncc1N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccncc1Nc1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
To a solution of 0.134 g (1.08 mmol) of 3-amino-4-methoxypyridine in THF (3 mL) was added 0.5 mL of butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 15 min. A solution of 0.133 g (0.36 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2/EtOAc (2:3) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.078 g (48% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 161-163° C.; 1H NMR (DMSO-d6) δ9.43 (br s, 1H), 8.61-8.37 (m, 3H), 7.83-7.81 (m, 2H), 7.41 (br s, 2H), 7.20 (d, J=5.6 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); Anal. Calcd. for C21H20F2N8O2: C, 55.5; H, 4.4; N, 24.7. Found: C, 55.5; H, 4.4; N, 24.5%.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:31])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20](Cl)[C:21]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:22]=3[N:23]=2)=[CH:14][CH:13]=1>>[CH3:9][O:10][C:11](=[O:31])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]3[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[S:24][C:22]=3[N:23]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc([N+](=O)[O-])sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccccc3)c3cc([N+](=O)[O-])sc3n2)cc1

Procedure:
The reaction procedure as above wherein benzylamine is reacted with 4-(4-chloro-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH3:56][N:55]([CH3:57])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:50])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Agent: F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MEOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2O2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[N:10]2[C:29](OC2C=CC([N+]([O-])=O)=CC=2)=[O:30])[CH:5]=[CH:6][C:7]=1[F:8].Cl.Cl.[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][C:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]#[N:62])([C:53]#[N:54])[CH2:49][CH2:48]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[N:10]2[C:29](=[O:30])[NH:43][CH2:44][CH2:45][CH2:46][N:47]2[CH2:48][CH2:49][C:50]([C:53]#[N:54])([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:61]#[N:62])[CH2:51][CH2:52]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN2C(=O)N(C(=O)Oc3ccc([N+](=O)[O-])cc3)C(c3ccc(F)c(F)c3)c3ccccc32)cc1
Reactant: N#Cc1ccccc1C1(C#N)CCN(CCCN)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C(=O)N(C(=O)NCCCN3CCC(C#N)(c4ccccc4C#N)CC3)C(c3ccc(F)c(F)c3)c3ccccc32)cc1
Reaction time: 2 h

Procedure:
To a solution of 11 (0.060 g, 0.109 mmol) in 10 ml of CHCl3 was added N-(3-amino)propyl-4-(2-cyanophenyl)-4-cyanopiperidine dihydrochloride (Example 1) and diisopropyl ethylamine (0.057 mL, 0.329 mmol). The resulting solution was stirred for 2 hours and the crude material purified by PCTLC (5% MeOH in CHCl3/2%NH4OH) affording the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13]=2[CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=1.[CH3:36][NH2:37]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:37][CH3:36])[CH2:14][C:13]=2[CH:12]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=1
Reactant: CN
Reactant: COc1ccccc1-c1cc(-c2ccccc2)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccccc3OC)c2O1

Procedure:
The title compound was prepared (0.060 g, 76%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 140-143° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4-benzyloxy-3-hydroxybenzaldehyde (5 g, 21.9 mmol) in DMF (50 mL) was added cyclopentyl bromide (4.7 mL, 43.8 mmol) and K2CO3 (12.1 g, 87.6 mmol). The reaction mixture was stirred at r.t. overnight. K2CO3 was then filtered from the mixture. The mixture was extracted with EtOAc, and the organic layer was washed with water (2×) and then brine, and finally dried over Na2SO4. The product was concentrated under reduced pressure and purified by silica gel to provide a colorless oil which solidified to a white solid upon standing. Yield: 98%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[CH2:10]([SH:12])[CH3:11].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH2:10][CH3:11])=[CH:4][C:3]=1[Cl:9]
Reactant: Fc1ccc(Br)c(Cl)c1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSc1ccc(Br)c(Cl)c1
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 1-bromo-2-chloro-4-fluorobenzene (24.8 g, 119 mmol) and ethanethiol (10.6 mL, 143 mmol) in N,N-dimethylformamide (150 mL) was added sodium hydride (60% in oil, 6.00 g, 150 mmol) at room temperature by small portions, and the resulting mixture was stirred for 4 hr. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the title compound (19.4 g, yield 65%) as a colorless oil.
Reaction SMILES: Br[CH:2]1[CH2:14][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:4]2[C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CC(C)=O>[N:16]([CH:2]1[CH2:14][N:5]2[CH2:6][CH2:7][CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:4]2[C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C1CCCN2CC(Br)C(=O)N12
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1CCCN2CC(N=[N+]=[N-])C(=O)N12
Yield: 27.8 %

Procedure:
4.5 g of methyl 2-bromo-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (2 racemates) and 1.58 g of sodium azide in 30 ml of acetone were stirred and heated under reflux for 48 hours. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel. Elution with diethyl ether/methanol (19:1, v/v) gave firstly 2.5 g (65%) of methyl 2-azido-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (racemate A) in the form of a white solid of melting point 92°-93° C. (from ethyl acetate/n-hexane) and secondly 1.08 g (28%) of methyl 2-azido-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (racemate B) in the form of a white solid of melting point 70°-71.5° C. (from diethyl ether/n-hexane).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][CH2:47][CH:48]([OH:50])[CH3:49]>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:46]([CH2:47][CH:48]([OH:50])[CH3:49])[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:13]=2[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(CC(C)O)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 63.1 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylic acid (639 mg, 1 mmol) and 1-amino-2-propanol (0.19 g, 2.5 mmol) gave the title compound (409.7 mg, 63%) as colorless crystals.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6](OC)=[C:7](OC(=O)C)[C:8](=[O:13])[N:9]2C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:13]
Reactant: COc1c(OC(C)=O)c(=O)n(C)c2cc(N)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: O=c1ccc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a mixture of 0.95 g of 7-amino-3-acetoxy-4-methoxy-1-methyl-2(1H)-quinolinone (3.6 mmol) in 20 ml of DMF were added 0.55 g of potassium carbonate (4.0 mmol) and 0.56 g of methyl iodide (4.0 mmol) and stirred at room temperature for 1 hour. The reaction mixture was added to water and extracted with toluene, the organic layer was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (hexane/ethyl acetate=1/1 as an eluent) gave 0.45 g of the title compound (9). (yield=45%)
Reaction SMILES: [F-].[Cs+].C(=O)([O-])[O-].[Cs+].[Cs+].C([Si]([S:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)(C(C)C)C(C)C)(C)C.[C:28]([CH2:30][NH:31][C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:40]Br)=[O:33])#[N:29]>CN(C)C=O.ClCCl>[C:28]([CH2:30][NH:31][C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:40][S:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[CH:24][CH:25]=1)=[O:33])#[N:29]
Reactant: CC(C)[Si](Sc1ccc(CO)cc1)(C(C)C)C(C)C
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Cesium fluoride (0.829 g, 5.46 mmol) and cesium carbonate (0.456 g, 1.4 mmol) were added to a stirred solution of (4-triisopropylsilanylsulfanyl-phenyl)-methanol (0.808 g, 2.73 mmol) and trans-2-bromomethyl-cyclohexanecarboxylic acid cyanomethyl amide (0.906 g, 3.50 mmol) in dry dimethylformamide (910 mL). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was diluted with dichloromethane and washed with 1N HCl, then with saturated aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation to yield trans-N-cyanomethyl-2-(4-hydroxymethyl-phenylsulfanylmethyl)-cyclohexanecarboxamide as a white solid that was carried forward without further purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:8]=2[N:9]([CH3:11])[N:10]=1)=[O:5].[OH-:19].[Na+]>CCO>[CH3:11][N:9]1[C:8]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][C:7]=2[C:6]([C:4]([OH:5])=[O:19])=[N:10]1
Reactant: [OH-]
Reactant: CON(C)C(=O)c1nn(C)c2c1CCCCC2=O
Agent: [Na+]
Solvent: CCO
Product: Cn1nc(C(=O)O)c2c1C(=O)CCCC2

Procedure:
To a solution of N-methoxy-N,1-dimethyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide (14 mg, 0.055 mmol) in EtOH (1 mL), a solution of NaOH (2M, 55 μL) was added. The reaction was stirred under reflux for 1 h, the solvent was removed under vacuum, then DCM (5 mL) was added and the organic phase was washed with HCl 25% (3×5 mL). The aqueous phase was back-extracted with DCM (5 mL). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated under vacuum to give 11 mg of a white solid (quantitative yield).