Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].C1COCC1.Cl[Si](C)(C)C.[C:42]1([CH2:48][C:49](Cl)=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:49](=[O:50])[CH2:48][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:8]([OH:10])=[O:9]
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(O[C@H](C(=O)O)[C@]2(c3ccccc3)c3ccccc3CCN2C(=O)Cc2ccccc2)c1
Yield: 46.8 %

Procedure:
To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (60 mg, 0.143 mmol, Example 1) in THF (5 ml) Hünig's base (122 μl, 0.715 mmol) followed by chlorotrimethylsilane (22 μl, 0.172 mmol) is added at 5° C. The mixture is stirred at 55° C. for 3 h before phenylacetylchloride (29 μl, 0.215 mmol) is added. Stirring is continued at rt for 2 h before water (approx. 200 μl) is added. The mixture is diluted with DCM, washed twice with 2 N aq. HCl. The organic phase is dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC on Rp-C18 silica gel to give (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-2-phenylacetyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (36 mg) as a white powder. LC-MS1: tR=0.98 min, [M+1]+=538.13.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[C:9]([O:13][C:14](=[O:17])[CH2:15][Br:16])([CH3:12])([CH3:11])[CH3:10]>>[BrH:16].[C:9]([O:13][C:14](=[O:17])[CH2:15][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]1=[NH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1nc(N)sc1C
Reactant: CC(C)(C)OC(=O)CBr
Product: Br
Product: Cc1sc(=N)n(CC(=O)OC(C)(C)C)c1C
Temperature: 85 °C

Procedure:
A mixture of 4,5-dimethyl-thiazol-2-ylamine (1.0 g, 7.8 mmol) and bromoacetic acid tert-butyl ester (1.4 mL, 9.4 mmol) was heated at 85° C. for 14 hours and then cooled to ambient temperature. Recrystallization of the residue from ethyl acetate provided 2.9 g of a 4:1 mixture of the title compound to starting 4,5-dimethylthiazol-2-ylamine.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11]2)=[N:6]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH2:14])=[CH:11]2)=[N:6]1
Reactant: CN(C)CCn1cc2cc([N+](=O)[O-])ccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CCn1cc2cc(N)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethyl-[2-(5-nitro-indazol-2-yl)-ethyl]-amine (0.300 g, 1.28 mmol), iron powder (0.715 g, 12.8 mmol) and ammonium chloride (0.0343 g, 0.641 mmol) was suspended in a 4:1 ethanol/H2O solution. The mixture was heated to reflux for 3 hours, cooled to room temperature and the solvents were removed under vacuo. The residue was stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes, filtered through a plug of silica gel followed by rinsing with triethylamine/ethyl acetate (1/4). The filtrate was concentrated to provide the titled product. 1H NMR (300 MHz, DMSO-d6) ppm 2.16 (s, 6H) 2.72 (t, 2H, J=6.44), 4.35 (t, 2H, J=6.44), 4.74 (s, 2H), 6.55 (dm, 1H), 6.72 (m, 1H), 7.30 (m, 1H), 7.89 (s, 1H); MS (DCI/NH3) m/z 205 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].CC(O)=O.C1C(=O)N([Br:20])C(=O)C1.O>C(Cl)(Cl)Cl>[Br:20][C:5]1[S:1][C:2]([CH2:6][CH2:7][OH:8])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCc1cccs1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: OCCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(thiophen-2-yl)ethanol (3 g, 23.4 mmol, 1 eq) and HOAc (5 mL) in CHCl3 was added NBS in portions at room temperature. After stirring at room temperature overnight, the reaction mixture was poured into water and extracted with CHCl3 twice. The combined organic layer was dried over Na2SO4, concentrated and purified by column chromatography to give the desired product.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](O[K])C.ClC[CH:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][Si:16]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:18]>C(O)C>[CH3:22][O:21][Si:16]([O:17][CH3:18])([O:19][CH3:20])[CH2:15][CH2:14][C:23]1[CH:24]=[CH:25][C:26]([CH2:8][S:1][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:28]=1
Reactant: CO[Si](CC(CCl)c1ccccc1)(OC)OC
Reactant: Sc1ncccn1
Reactant: CCO[K]
Solvent: CCO
Product: CO[Si](CCc1ccc(CSc2ncccn2)cc1)(OC)OC
Reaction time: 0.08 h
Yield: 73 %

Procedure:
10 mmole of 2-mercaptopyrimidine was dissolved in 20 ml ethanol, then 10 mmole EtOK was added, and stirred for 5 minutes. 10 mmole of ((chloromethyl)phenylethyl)trimethoxysilane was added to the solution, and stirred for 6 hours. The white precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The obtained viscous liquid was separated with a Si gel column (solvents: 1 ethylacetate/3 hexane). 1H NMR (CD3Cl): δ(ppm) 8.50 (2H, m, Pyr.-H), 7.25 (4H, m, Ar—H), 6.95 (1H, m, Pyr.-H), 4.38 (2H, s —CH2—), 3.54 (9H, s, —CH3), 2.70 (2H, m, —CH2—), 0.99 (2H, m, —CH2—). Yield: 73%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[CH:5][O:6][CH:7]([F:9])[F:8].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][Br:36])=[CH:5][O:6][CH:7]([F:8])[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(=COC(F)F)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=COC(F)F)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A solution of 14.2 g of 3-difluoromethoxy-2-(o-tolyl)-acrylic acid methyl ester and 0.15 g of dibenzoyl peroxide in 85 ml of carbon tetrachloride is heated to reflux. With radiation from a lamp, 10.44 g of N-bromosuccinimide are then added in several small portions and the reaction mixture is left to react for 1.5 hours. After cooling to room temperature, the reaction mixture is filtered and concentrated by evaporation in vacuo. The pale red crude product is purified by chromatography on silica gel with hexane/ethyl acetate and crystallised from hexane. Pure 2-(2-bromomethylphenyl)-3-difluoromethoxy-acrylic acid methyl ester is obtained; m.p. 63°-67° C.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[C:8]2[N:7]=CC(O)=[CH:4][C:3]=2[CH:2]=1.[N+](=[CH2:15])=[N-].C[CH2:17][O:18][CH2:19][CH3:20]>C(O)C>[CH3:17][O:18][C:19]1[CH:20]=[N:7][C:8]2[C:3]([CH:4]=1)=[CH:2][CH:1]=[CH:10][C:9]=2[O:11][CH3:15]
Reactant: Oc1cnc2c(O)cccc2c1
Reactant: C=[N+]=[N-]
Reactant: CCOCC
Solvent: CCO
Product: COc1cnc2c(OC)cccc2c1
Yield: 80 %

Procedure:
Jineol of 4.5 mg was dissolved in 2 ml of ethanol, and diazomethane ether solution was slowly dropped to the solution. After the excess of diazomethane and solvent was removed by purging with nitrogen gas, the solution was purified by silicagel chromatography to give 4.2 mg of 3,8-dimethoxy quinoline with 80% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:24]([Cl:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].Cl.C(OCC)C>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])[C:24]([Cl:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)(=O)C(C)C)cc3n2COCCOC)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)(=O)C(C)C)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of 1-[5-chloro-1-(2-methoxy-ethoxymethyl)-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.243 g, 0.501 mmol) in ethanol (1.8 mL) was added 4M HCl in dioxane (1.8 mL). The reaction mixture was stirred at 23° C. for 1.5 h. Diethyl ether was added and the precipitate collected to yield the titled compound (0.183 g, 92% yield). MS (ESI/CI): mass calcd. for C16H17ClN4O4S, 369.1; m/z found, 397.1 [M+H]+. 1H NMR (400 MHz, DMSO): 9.03 (d, J=0.6 Hz, 1H), 8.42 (d, J=0.6 Hz, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.89-3.76 (m, 1H), 1.33 (t, J=7.1 Hz, 3H), 1.21 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[C:5]([F:12])=[C:4]([CH3:13])[N:3]=1.[S:14]1[C:18]([C@:19]23[CH2:27][NH:26][CH2:25][C@H:24]2[CH2:23][S:22][C:21]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:20]3)=[CH:17][CH:16]=[N:15]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:12][C:5]1[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:7][C:2]([N:26]2[CH2:25][C@@H:24]3[C@@:19]([C:18]4[S:14][N:15]=[CH:16][CH:17]=4)([N:20]=[C:21]([NH:28][C:29](=[O:36])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[S:22][CH2:23]3)[CH2:27]2)=[N:3][C:4]=1[CH3:13]
Reactant: Cc1nc(Cl)nc(C(C)(C)O)c1F
Reactant: O=C(NC1=N[C@@]2(c3ccns3)CNC[C@H]2CS1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccns3)C2)nc(C(C)(C)O)c1F
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 17.8 %

Procedure:
2-(2-Chloro-5-fluoro-6-methyl-pyrimidin-4-yl)propan-2-ol (104 mg, 0.51 mmol) is dissolved in 1,4-dioxane (3 mL). N-[(4aR,7aR)-7a-Isothiazol-5-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (125 mg, 0.36 mmol) is added followed by diisopropylethylamine (158 μL, 0.91 mmol). The reaction is heated via microwave irradiation in a sealed microwave vessel to 110° C. for 1 hr. The reaction is concentrated to give the crude product. The crude product is purified via HPLC using a Waters XBridge 5 μm C18 OBD 30×75 mm column and eluted with a gradient of: 36% β isocratic for 3 min followed by 36-51% B over 5 min where solvent A is 10 mM ammonium bicarbonate in water with 5% MeOH and solvent B is acetonitrile. The desired fractions are combined and diluted with saturated NaHCO3 (aq, 100 mL). The mixture is extracted with 4:1 CHCl3: isopropanol (3×100 mL). The organic layers are combined, washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to give the title compound (33 mg, 0.064 mmol): EZ/MS (m/z): 513 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[C:34]1([NH2:41])[C:35]([NH2:40])=[CH:36][CH:37]=[CH:38][CH:39]=1>>[NH:40]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:41]=[C:16]1[CH:9]1[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Reactant: Nc1ccccc1N
Product: N#CC=C1CC(c2nc3ccccc3[nH]2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 1,2-benzenediamine the title compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=405.2.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.CCCCCC.[F:18][CH:19]([F:40])[C:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([CH:34]=[O:35])=[C:22]([C:36]([F:39])([F:38])[F:37])[N:21]=1.Cl>C1COCC1.O>[F:40][CH:19]([F:18])[C:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([CH:34]([OH:35])[C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)=[C:22]([C:36]([F:39])([F:37])[F:38])[N:21]=1
Reactant: Brc1ccsc1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2ccsc2)c1CC(C)C
Temperature: -70 °C
Yield: 67.8 %

Procedure:
To a solution of 3-bromothiophene (4 g 24.5 mmol) in dry THF (80 mL) cooled to -70° C. was added dropwise 2.5M n-BuLi in hexane (11 mL, 27.5 mmol). The mixture was stirred for one-half h. A solution of methyl 2-(difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (6.6 g, 19.5 mmol) in anhydrous THF (20 mL) was added dropwise and stirring was continued for I h while the temperature was maintained at -70° C. The mixture was allowed to warm to RT and then poured into iced water, acidified with conc. HCl and extracted with methylene chloride. The extract was washed with water and brine, dried (MgSO4), and conc. The residue was purified by chromatography with 10% ethyl acetate/cyclohexane to yield 5.6 g of methyl 2-(difluoromethyl)-5-(hydroxy-3-thienylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate, a 68.9% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.CC(C)([O-])C.[K+].[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][C:26]=1[O:33][CH:34]([F:36])[F:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(O)(C)(C)C>[CH2:17]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]2[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[CH:27][C:26]=1[O:33][CH:34]([F:35])[F:36])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)Oc1cc(CCl)ccc1OCc1ccccc1
Reactant: Cc1nc(C)c(Cl)c(N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OC(F)F)c2)n1

Procedure:
In analogy to the method described in example A5, 3.8 g (22.7 mmol) of 4-amino-5-chloro-2,6-dimethylpyrimidine, 2.8 g (25 mmol) of potassium tert-butoxide and 6.8 g (22.7 mmol) of 4-benzyloxy-3-(1,1-difluoromethoxy)benzyl chloride are reacted in 15 ml of tert-butanol and 15 ml of toluene and the product is worked up. After chromatography on silica gel (mobile phase: toluene/dioxane=5:1), the title compound is obtained as a viscous, colorless oil. 1H NMR spectrum (CDCl3, δ ppm): 7.5-7.3 (m, 5H), 7.19 (m, 1H), 7.12 (dd, 1H), 6.58 (t, 1H, J=80 Hz), 5.58 (tb, NH), 5.13 (s, 2H), 4.63 (d, 2H), 2.51 (s, 3H), 2.43 (s, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].[CH:14](Br)([CH3:16])[CH3:15].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23]>C1(C)C=CC=CC=1.C(N(CCOCCOC)CCOCCOC)COCCOC.O>[CH2:24]([N:22]([CH3:23])[CH2:21][CH2:20][CH2:19][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH:14]([CH3:16])[CH3:15])[C:10]#[N:11])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(CC#N)c1
Reactant: CN(CCCCl)CCc1ccccc1
Reactant: CC(C)Br
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(C(C#N)(CCCN(C)CCc2ccccc2)C(C)C)c1
Reaction time: 2 h
Yield: 71.6 %

Procedure:
13.5 g (0.1 mole) of 3-methoxyphenylacetonitrile were dissolved in 15 ml of toluene, and 52 g (0.8 mole) of 85% strength potassium hydroxide powder and 0.2 g of tris(3,6-dioxaheptyl)-amine were added. Thereafter, 12.3 g (0.1 mole) of isopropyl bromide were added dropwise to the stirred mixture at a rate such that the reaction temperature did not exceed 50° C. When the addition was complete, stirring was continued for 2 hours at 50° C., after which a solution of 21.2 g (0.1 mole) of N-(3-chloropropyl)-N-methylphenethylamine in 20 ml of toluene was added at 90° C. The reaction mixture was stirred for a further 3 hours at 90° C. and cooled, after which 100 ml of water were added and the toluene phase was separated off. The toluene was distilled off to give a yellow oil, which was chromatographed over a silica gel column using a solvent mixture consisting of 9:1:0.5 methylene chloride/acetone/ methanol. The chromatographically pure base was dissolved in ethyl acetate, and the hydrochloride was precipitated with ethanolic hydrochloric acid. 26.1 g (65%) of a product of melting point 154°-156° C. were obtained.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[S:10][C:9]2=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][N:8]2[CH:7]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>O>[Br:5][C:6]1[S:10][C:9]2=[N:11][C:12]([C:14]([N:17]=[N+:18]=[N-:19])=[O:16])=[CH:13][N:8]2[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cn2cc(Br)sc2n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Thionyl chloride (0.33 mol) was added to 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid (13.1 mmol). The reaction mixture was stirred at 85° C. during 3 hrs. The mixture was then concentrated under vacuum and the residue was taken in acetone (40 mL). The sodium azide (14.4 mmol) in water (5.2 mL) was added in one portion at 0° C. and the mixture was stirred at 0-10° C. for 45 min. Water was added, and the solid filtered off and washed with water and then with a mixture of water/acetone (50/50). The solid was dried in vacuo to give compound 9 as a beige solid in 80% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.27 (s, 1H), 8.49 (s, 1H); and MS (ESI, EI+) m/z=272.05-274.07 (MH+).
Reaction SMILES: [C:1]([CH:3]1CCCC1)#[CH:2].[N+:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:10])=O.C([OH:19])C>C1N2CCN(CC2)C1>[OH:19][CH2:3][C:1]1[O:10][N:8]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1
Reactant: CCO
Reactant: C#CC1CCCC1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Product: CCOC(=O)c1cc(CO)on1
Temperature: 80 °C
Yield: 96 %

Procedure:
To a mixture of ethynylcyclopentane (0.74 mL; 6.05 mmol) and ethyl 2-nitroacetate (1.37 mL; 12.11 mmol) in ethanol (9 mL) in an Ace pressure tube was added 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.070 g; 0.60 mmol). The tube was heated at 80° C. for 96 h. The mixture was evaporated. The flash chromatography on silica gel (eluent: 20 to 80% dichloromethane in heptane) of the residue provided 1.21 g (96%) of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Cl:7])([O-:3])=[O:2].[NH2:12][C:13]([NH2:15])=[S:14].C(O)C>ClCCCC>[ClH:7].[C:13]([S:14][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[NH:12])[NH2:15]
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1ccccc1CCl
Solvent: CCO
Solvent: CCCCCl
Product: Cl
Product: N=C(N)SCc1ccccc1[N+](=O)[O-]
Yield: 83.7 %

Procedure:
A solution of 153.9 g of o-nitrobenzylchloride and 68.5 g of thiourea in 900 ml of #2B ethanol was stirred at reflux temperature (80°) for 11/4 hours. The solution was cooled to 60° and 1.1 liters of 1-chlorobutane was added. Further cooling to 15° produced a heavy precipitate. The precipitate was filtered, washed with 1-chlorobutane and dried to yield 185.9 g of 2-nitrophenylmethyl carbamimidothioate hydrochloride, m.p. 190°-192°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:24][CH2:25][C:26]2[N:27]([CH3:31])[N:28]=[CH:29][N:30]=2)=NN2[C:16]=1[CH:15]=[N:14][N:13]=C2C1C=CC=CC=1F.[F:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([NH:39][NH2:40])=O)=[CH:35][CH:34]=1.[CH2:43](N1C(CO)=NC=N1)C>>[CH2:31]([N:27]1[C:26]([CH2:25][O:24][C:9]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:16]3[N:39]([C:37]([C:36]4[CH:41]=[CH:42][C:33]([F:32])=[CH:34][CH:35]=4)=[N:13][N:14]=[CH:15]3)[N:40]=2)=[N:30][CH:29]=[N:28]1)[CH3:43]
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccc1F
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: CCn1ncnc1CO
Product: CCn1ncnc1COc1nn2c(-c3ccc(F)cc3)nncc2c1-c1ccccc1F

Procedure:
This compound was prepared using the procedure described in Example 21, steps b) to f), using 3-(2-fluorophenyl)-4-hydroxy-2-furanone (cf Example 2) instead of 3-tert-butyl-4-hydroxy-2-furanone, 4-fluorobenzoic hydrazide instead of 2,5-difluorobenzoic hydrazide in step e) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol instead of (2-methyl-2H-[1,2,4]triazol-3-yl)methanol in step f). Data for the title compound: mp=179° C.; 1H NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J=7.4 Hz), 4.23 (2H, m), 5.67 (2H, s), 7.22-7.32 (4H, m), 7.39-7.44 (1H, m), 7.57 (1H, m), 7.92 (1H, s), 8.54-8.58 (2H, m), 9.21 (1H, s); MS (ES+) m/e 434 [MH]+; Anal. Found: C, 60.86; H, 3.83; N, 22.30%. C22H17F2N7O requires: C, 60.97; H, 3.95; N, 22.62%.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([O:16][CH3:17])[C:7]1=2)C.[OH-].[Li+].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([O:16][CH3:17])[C:7]=2[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(OC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a solution of ethyl-2-(1,6-dihydroxy-4-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (133 mg, 0.50 mmol) in THF (2 mL) was added aqueous lithium hydroxide (102 mg, 2.5 mmol) in 3 mL of water at 0° C. The reaction mixture was stirred at room temperature for 1.5 hr and acidified to pH=2 using diluted hydrochloride acid. The resulting mixture was extracted with ethyl acetate (15 mL×2) and the combined organic layers were dried over anhydrous and concentrated in vacuo. The residue was purified by HPLC to give the title as a white solid (63 mg, Yield: 53%). 1H NMR (400 MHz, DMSO-d) δ 9.49 (s, 1H), 9.15 (s, 1H), 6.65 (s, 1H), 6.48 (s, 1H), 5.31-5.34 (m, 1H), 3.77 (s, 3H), 3.04-3.09 (m, 1H), 1.98-2.04 (m, 1H). MS (ESI) m/z=239 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Br:30])[C:19]=1[Cl:31].CC(=O)OCC>CN(C=O)C>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Br:30])[C:19]=1[Cl:31]
Reactant: C=C(c1cc(Br)c(Cl)c(Br)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Br)c(Cl)c(Br)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (68 mg, 0.28 mmol) in DMF was added 1,3-dibromo-2-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (132 mg, 0.36 mmol) and TEA (31 mg, 0.36 mmol) at rt. The mixture was stirred at 25° C. for 12 h, quenched with water, extracted with EA (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluted with PE:EA=5:1 to give the final title compound 5-(5-(3,5-dibromo-4-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (38 mg; yield 22%) as solid. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.96 (s, 2H), 7.76-7.69 (m, 3H), 4.45-4.30 (q, 2H), 1.48 (s, 6H) ppm; MS: m/z=568 (M+1, ESI+).