Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][CH2:20][CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:19][CH2:20][CH2:21][CH2:22][S:23]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(CCCCl)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 3-chloropropane-1-sulfonyl chloride to obtain the desired product. 1H NMR (500 MHz, CDCl3): δ=7.39-7.38 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.10-7.0 (q, 1H), 6.63 (s, 1H, br), 6.15-6.11 (q, 1H), 5.60 (s, 1H, br), 3.60-3.56 (t, 2H), 3.22-3.20 (m, 2H), 2.22-2.16 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([OH:34])=O)[CH2:29][N:30]=1)=[CH:9]2.Cl.C[N:37](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([NH2:37])=[O:34])[CH2:29][N:30]=1)=[CH:9]2
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(N)=O)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.1 %

Procedure:
A mixture of (2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (90 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio) to give colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (80 mg, yield 55%) as a colorless powder. melting point 100-102° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:24](O)[CH2:25][OH:26].CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[C:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:5]3([C:8]#[N:9])[CH2:6][CH2:7][C:2]4([O:26][CH2:25][CH2:24][O:1]4)[CH2:3][CH2:4]3)=[CH:11][CH:12]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#CC1(c2ccc(OCc3ccccc3)cc2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccc(OCc3ccccc3)cc2)CCC2(CC1)OCCO2
Yield: 47 %

Procedure:
A mixture of 65 parts of 4-oxo-1-[4-(phenylmethoxy)phenyl]-1-cyclohexanecarbonitrile, 15.7 parts of 1,2-ethanediol, 0.2 parts of 4-methylbenzenesulfonic acid and 360 parts of methylbenzene is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, washed successively with water, with a sodium hydroxide solution 5% and again with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 33.5 parts (47%) of 8-[4-(phenylmethoxy)phenyl]-1,4-dioxaspiro[4,5]decane-8-carbonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>C(N(CC)CC)C>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)(=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Oc1ccc(C#N)cc1

Procedure:
This compound was prepared by reacting 4-hydroxybenzonitrile with valeryl chloride in the presence of triethylamine to give 4-cyanophenyl valerate which was subjected to a Fries rearrangement with aluminium chloride to give 4-hydroxy-3-valerylbenzonitrile which was reduced with sodium borohydride to give the title compound.
Reaction SMILES: [C:1]([C:4]([C@@:6]([C:20](=[O:22])[CH3:21])([C@:8]([C:17](=[O:19])[CH3:18])([C@H:10]([CH2:15][OH:16])[O:11][C:12](=[O:14])[CH3:13])[OH:9])[OH:7])=[O:5])(=O)[CH3:2].[C:23]1([SH:29])C=CC=C[CH:24]=1.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:29]1[CH:23]=[CH:24][CH:2]=[C:1]1[C:4]([C@@:6]([C:20](=[O:22])[CH3:21])([C@:8]([C:17](=[O:19])[CH3:18])([C@H:10]([CH2:15][OH:16])[O:11][C:12](=[O:14])[CH3:13])[OH:9])[OH:7])=[O:5]
Reactant: CC(=O)O[C@@H](CO)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)C(=O)C(C)=O
Reactant: Sc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H](CO)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)C(=O)c1cccs1
Temperature: -78 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
Dry 1,2,3,4-O-tetraacetyl-L-arabinose (18.3 g, 57.5 mmol) was dissolved in dry CH2Cl2 (200 mL) and was cooled to −78° C. Thiophenol (6.5 mL, 63.3 mmol) was added followed by addition of SnCl4 (1M, 17.3 mL, 17.3 mmol). The reaction solution was stirred at −78° C. for 6 hours until the disappearance of the starting material in TLC. Saturated aqueous NaHCO3 (100 mL) was added. The organic layer was separated and the water layer was extracted with CH2Cl2 (30 mL) three times. The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the product was purified by silica gel column chromatography to afford thiophenyl-2,3,4-O-triacetyl-L-arabinose (16.95 g, 80%). Thiophenyl-2,3,4-O-triacetyl-L-arabinose (8.88 g, 24.1 mmol) was dissolved in MeOH (120 mL) followed by the addition of sodium methoxide (65 mg, 2 mmol ). The reaction solution was stirred at 25° C. for three hours, then saturated aqueous NH4Cl was added. The organic layer was separated and the water layer was extracted with CH2Cl2 (30 mL) three times. The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the product was purified by silica gel column chromatography to afford 22 (5.53 g, 22.9 mmol, 95%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[CH3:16][O:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: COCC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: COCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 44.3 %

Procedure:
6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 3.9 g (35.9 millimoles) of methoxyacetyl chloride in 150 ml of absolute tetrahydrofuran were refluxed for 2 hours, while stirring. The product was filtered off under suction at 10° C., washed with water and recrystallized from dimethylformamide/water. 3.6 g (44%) of 6-[p-(methoxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained as colorless crystals. Mp.: 212° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)C(C)C)c(O)c21
Reaction time: 3 h
Yield: 105.1 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), isobutyryl chloride (42.5 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 3 hr. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (118 mg, yield 100%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([C:29](O)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>>[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([C:29]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CC(C)C[C@H]2CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available biphenyl-2-carboxylic acid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])=[O:32]
Reactant: O=C(CSc1nc2ccccc2s1)N1CCCc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(CS(=O)c1nc2ccccc2s1)N1CCCc2ccccc21
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of compound 64 (167 mg, 0.49 mmol) in DCM (4 mL) cooled in a salt-ice bath was added a solution of mCPBA (77%, 110 mg, 0.49 mmol) in DCM (4 mL) drop wise. The reaction mixture was stirred for 1 hr. After diluting with DCM (30 mL), the solution washed with Na2S2O3, NaHCO3, dried over Na2SO4 and concentrated in vacuum. The crude material was purified by flash chromatography on silica gel eluting with EtOAc/hexanes (20˜50%) to give compound 65 as a white solid (164 mg, 94%). MS (APCI): m/z 357 [M+H]+. Anal. Calcd for C18H16N2O2S2: C, 60.65; H, 4.52; N, 7.86. Found: C, 60.44; H, 4.66; N, 7.73.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=[O:28])[CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[H-].[Na+].[CH:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35].Cl>O1CCCC1.O>[O:28]=[C:7]([CH:8]=[CH:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCCCC=O
Reactant: CCOC(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC=CC(=O)CC(=O)OCC
Temperature: 45 °C
Yield: 40.2 %

Procedure:
To a solution of (3-ethoxycarbonyl-2-oxopropylidene)triphenylphosphorane (5.0 g, 12.8 mmol) in tetrahydrofuran (THF, 50 ml) were added sodium hydride (60% dispersion in oil, 1.03 g, 25.6 mmol) and then pentanal (1.10 g, 12.8 mmol) followed by stirring. After addition of water (three drops), the mixture was heated at 45° C. for 1 hour. The reaction mixture was treated with dilute hydrochloric acid and extracted with ether. The organic layer was washed with aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, dried (MgSO4), and concentrated to dryness. The resulting residue was purified by column chromatography on silica gel. The column was eluted with dichloromethane-hexane (1:1 to 3:2) to give 1.02 g (40.0%) of the title compound as an oil. The 1H-NMR spectrum indicates that the product is a mixture of keto/enol isomers.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:15].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N+:3]=1[O-:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(F)c(Br)n1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(F)c(Br)[n+]1[O-]
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To an ice-cold solution of 2-bromo-3-fluoro-6-picoline (1.00 g) in chloroform (25 mL) was added 3-chloroperoxybenzoic acid (1.77 g), and the mixture was stirred while warming to room temperature for 22 hr. After cooling in ice again, additional 3-chloroperoxybenzoic acid (590 mg) was added and the mixture was stirred while warming to room temperature for 21 hr. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the resulting mixture was then stirred. Thereafter, saturated aqueous sodium hydrogen carbonate solution and water were added thereto, followed by extraction with chloroform. The organic phase was washed with brine, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-0:100) to afford 2-bromo-3-fluoro-6-methylpyridine 1-oxide (604 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[N:15]([CH:22]([CH3:24])[CH3:23])[C:14]3=[O:25])[N:8]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[C-:32]#[N:33].[Na+]>CS(C)=O>[CH:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:13]([CH2:12][C:9]2[N:8]([CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][C:32]#[N:33])[C:11]=3[N:10]=2)[C:14]1=[O:25])([CH3:23])[CH3:24]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CCl)cccc21
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CC#N)cccc21

Procedure:
A solution containing 1-[4-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one; HCl salt (69 mg, 0.15 mmol) and sodium cyanide (30 mg, 0.62 mmol) in DMSO (1.5 mL) was stirred at room temperature for 1.5 h. The mixture was quenched with water (15 mL) and 1M NaOH (0.5 mL). The aqueous suspension was extracted with diethyl ether (2×10 mL) and the combined organic extracts washed with water, brine and dried (MgSO4). [2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-4-yl]-acetonitrile was obtained after concentration as a white solid (55 mg, 89%) and was used in the next step without purification:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:4]1[N:3]=[C:2]([NH:28][CH:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1

Procedure:
The title compound was prepared from 50 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2) and 63 mg of tert-butyl 4-aminopiperidine-1-carboxylate by a procedure analogous to that described in COMPOUND HHH4. Mass spectrum (ESI) 599 (M+1).
Reaction SMILES: [Br:1][C:2]([Br:13])=[CH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1.[CH2:14]([C:17]1([CH2:21][OH:22])[CH2:20][O:19][CH2:18]1)[CH2:15][CH3:16].N1C=CC=CC=1>ClCCl>[Br:1][C:2]([Br:13])=[CH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:22][CH2:21][C:17]2([CH2:14][CH2:15][CH3:16])[CH2:20][O:19][CH2:18]2)=[O:11])[CH2:6][CH2:5]1
Reactant: CCCC1(CO)COC1
Reactant: O=C(Cl)C1CCC(C=C(Br)Br)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(COC(=O)C2CCC(C=C(Br)Br)CC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
4-(2,2-Dibromovinyl)cyclohexanecarbonyl chloride (0.91 g) in dry dichloromethane (5 ml) was added to a cooled (0° C.) solution of 3-propyl-3-hydroxymethyloxetane (0.406 g) and pyridine (0.64 ml) in dry dichloromethane (10 ml) under a stream of nitrogen. The reaction mixture was allowed to warm to room temperature and to stir overnight. Further dichloromethane was added. The organic phase was then washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine before drying over anhydrous magnesium sulphate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel, pre-eluted with hexane containing 1% triethylamine. Elution with hexane/ether (3:1) gave 3-propyloxetan-3-ylmethyl 4-(2,2-dibromovinyl)cyclohexanecarboxylate (0.6 g) as a mixture of cis- and trans-isomers.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:8]2[N:19]=[CH:20][CH:21]=[C:7]2[N:6]=1)[CH2:2][CH:3]=[CH2:4].C1C(=O)N([Br:29])C(=O)C1.O>C(COC)OC.O>[Br:29][C:21]1[CH:20]=[N:19][N:8]2[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])=[N:6][C:7]=12
Reactant: C=CCCc1cc(OCc2ccncc2)n2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: COCCOC
Product: C=CCCc1cc(OCc2ccncc2)n2ncc(Br)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(3-Butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine (compound of Example 1), 500 mg, was dissolved in 10 ml of dimethoxyethane-water (3:1). The solution was cooled to 0° C. and 380 mg of NBS was added. The mixture was stirred at 0° C. for 1 hour and further stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crystals precipitated were collected by filtration. The crude crystals were recrystallized from dichloromethane-n-hexane to provide 440 mg of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [N:1]1([C:6]2[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[N:31]#[C:32]Br>C(Cl)(Cl)Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:32]#[N:31])[CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:23][CH:24]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNCC2)n1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (1.00 g, 2.92 mmol) and potassium carbonate (1.5 g, 10.9 mmol) in chloroform (25 mL) was added cyanogen bromide (0.371 g, 3.5 mmol). The slurry was refluxed for 48 hours then stirred at room temperature for an additional 48 hours. The reaction was filtered through a pad of celite, concentrated and chromatographed on silica gel (1:1 Hexanes/EtOAc) to afford the desired compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[NH3:18]>C1(C)C=CC=CC=1>[CH:17]1[C:5]2[CH:4]=[C:3]([CH2:2][NH2:18])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[CH:15][CH:16]=1
Reactant: N
Reactant: BrCC1=Cc2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: NCC1=Cc2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
1.0 g (3.48 mmol) of 10-bromomethyl-dibenz[b,f]oxepine in 3 ml of toluene is added dropwise at 40° C. to 30 ml of NH3 -saturated methanol and the mixture is stirred at 35°-50° C. for 1 hour and at room temperature overnight. The solvent is partially removed, and the reaction mixture is taken up in tert-butyl methyl ether, washed with 0.1N sodium hydroxide solution and extracted with 1N hydrochloric acid. The aqueous phase is rendered basic with sodium hydroxide pellets and extracted with tert-butyl methyl ether, the organic phase is dried over sodium sulfate and the solvent is removed. 349 mg (1.56 mmol)=45% of N-(dibenz[b,f]oxepin-10-ylmethyl)amine are obtained in the form of a light-yellow oil; TLC (silica gel; ethyl acetate; UV): Rf =0.09.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:35])([F:34])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=4)[NH2:30])[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1.[C:36](O)(=[O:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[F:35][C:11]([F:10])([F:34])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:30][C:36](=[O:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1
Reactant: CC(=O)O
Reactant: Nc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
DIPEA (123 μl, 0.70 mmol) was added to 3-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]aniline (obtained as described in Example 616) (85 mg, 0.23 mmol), acetic acid (16 μl, 0.28 mmol) and HATU (107 mg, 0.28 mmol) in DMA (2 mL). The resulting solution was stirred at ambient temperature for 2 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to give N-[3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (89 mg, 94%) as a solid.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[S:3]([CH3:6])(=[O:5])=[O:4].[Cl-].[NH4+].C1COCC1>CO.[Zn]>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:16]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[O:17])=[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[CH:12]=1
Reactant: CN(c1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cc(N)ccc1C(=O)N1CCOCC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A suspension of N-methyl-N-(2-(morpholine-4-carbonyl)-5-nitrophenyl)methanesulfonamide (101.3 mg, 0.295 mmol), zinc (193 mg, 2.95 mmol), ammonium chloride (158 mg, 2.95 mmol) in MeOH (0.5 mL), and THF (0.5 mL) was stirred at room temperature for 16 h. The crude material was loaded onto a silica gel cartridge and dried in vacuo. The dry cartridge was then connected to an ISCO cartridge, eluting with 2-10% MeOH in CH2Cl2 to give the desired product as white solid (68.2 mg, 74% yield). LCMS: (M+H)+=314.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.94 (1H, d, J=8.28 Hz), 6.61 (1H, br. s.), 6.53 (1H, dd, J=8.28, 2.01 Hz), 5.52 (2H, s), 3.51 (4H, br. s.), 3.19-3.26 (1H, m), 3.15-3.18 (3H, m), 3.08 (3H, br. s.), 3.03 (3H, br. s.).
Reaction SMILES: CO[C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[C:5](OC)=[C:6](OC)[C:7]([OH:9])=[O:8].[OH-].[Na+].N#N>CS(C)=O>[C:7]([OH:9])(=[O:8])[CH:6]=[CH:5][C:4]1[CH:3]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(C(=O)O)=C(OC)c1ccccc1OC
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)C=Cc1ccccc1
Reaction time: 3 h

Procedure:
4.35 g of trimethoxy cinnamic acid and 100 mg of sodium hydroxide were dissolved in 5 ml of DMSO, and the mixture was stirred and heated to 90° C. under a flow of N2 gas. Water in the system was removed under low pressure condition. 10 g of glycidol was added, heating and agitation was carried out for 3 hours, and then the adduct of cinnamic acid and glycerin was obtained.