Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])[CH2:6][CH2:5]1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+].Cl>CC(O)C.O>[C:1]([C:4]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:23])[C:19]([OH:21])=[O:20])[CH2:5][CH2:6]1)([OH:3])=[O:2]
Reactant: CC(C)(CCCCCC(=O)CCCCCC1(C(=O)O)CC1)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(CCCCCC(O)CCCCCC1(C(=O)O)CC1)C(=O)O
Reaction time: 0.08 h
Yield: 107.9 %

Procedure:
To a mixture of 13-(1-carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (3.67 g, 10.8 mmol) in iPrOH (20 mL) and H2O (20 mL) was added NaOH (0.90 g, 22.5 mmol). After 5 min of stirring, NaBH4 (0.20 g, 5.3 mmol) was added to the resulting clear solution. Additional NaBH4 (0.10 g) was added after 100 min of stirring. After 16 h, the mixture was acidified to pH˜1 with aqueous HCl (1M) and extracted with Et2O (3×50 mL). The combined organic phases were washed with brine (2×50 mL), dried (Na2SO4), evaporated in vacuo and coevaporated in vacuo from EtOAc (2×15 mL) to give 13-(1-carboxycyclopropyl)-8-hydroxy-2,2-dimethyltridecanoic acid (3.99 g, 97%, contains 10% (w/w) EtOAc) as a viscous colorless oil. 1H NMR (CD3OD): δ=3.48 (m, 1H), 1.50-1.21 (m, 20H), 1.14 (s, 6H), 1.14-1.12 (m, 2H), 0.70 (dd, J=3.9, 6.3 Hz, 2H). 13C NMR (CD3OD): δ=181.6, 179.0, 72.4, 43.2, 42.0, 38.6, 38.5, 35.2, 31.5, 31.2, 28.9, 26.94, 26.87, 26.3, 25.94, 25.92, 24.4, 13.67, 16.36. HRMS calcd for C19H35O5 (M+H)+: 343.2484, found 343.2487.
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)Cl.[Br:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17]C)[CH:13]=2)[CH:8]=1.Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH:12]=[O:17])=[C:3]([O:2][CH3:1])[CH:11]=[CH:10]2
Reactant: COC(Cl)Cl
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2cc(Br)ccc2c1C=O
Temperature: 25 °C

Procedure:
9.7 ml of TiCl4 (2.1 eq) and 4.2 ml of dichloromethyl methyl ether (1.1 eq) are dissolved in 20 ml of dichloromethane at 0° C. A solution of 10 g of 2-bromo-6-methoxynapthalene (1 eq) is added dropwise in such a way that the temperature does not exceed 5° C. The reaction mixture is stirred at RT over night, followed by the addition of 300 ml of 1% HCl. The organic and aqueous phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness on a rotary evaporator to obtain the desired product in quantitative yield (11 g).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[CH:13]=[C:12]3[C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[CH2:4][O:3]1.Cl>CO>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])=[CH:17][CH:16]=2)[C:12]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:13]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OC[C@@H]5COC(C)(C)O5)cc34)cc3cccnc32)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OC[C@H](O)CO)cc34)cc3cccnc32)cc1
Yield: 39.5 %

Procedure:
A solution of 2-[5-({R}-(−)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [1.04 g, Reference Example 23(b)] in methanol (20 mL) was treated with hydrochloric acid (20 mL, 1M) then heated under reflux for 3 hours. The reaction mixture was concentrated in vacuo and the residue subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (2:1, v/v) to give the title compound (380 mg) as a clear oil. TLC: RF=0.2 (pentane/ethyl acetate: 1/2). MS: 492 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[C:28]([O:32][C:33]([N:35]([CH:49]([CH3:51])[CH3:50])[CH2:36][C:37]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)([OH:41])[C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([C:37]([OH:41])([C:38]([N:25]2[CH2:26][CH2:27][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:23][CH2:24]2)=[O:39])[CH2:36][N:35]([CH:49]([CH3:50])[CH3:51])[C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:47][CH:46]=1
Reactant: CC(C)N(CC(O)(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(CC(O)(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 59 %

Procedure:
DIPEA (35.5 mg, 0.275 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.69 mmol), 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid (29.5 mg, 0.082 mmol), and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5.0 mL) at room temperature. The resulting mixture was stirred overnight, diluted with EtOAc, washed with saturated aqueous. NaHCO3 and saturated aqueous NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g) and eluted by a mixture of EtOAc and hexane (60:40) to give tert-butyl 2-(4-chlorophenyl)-2-hydroxy-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a clear oil (27 mg, 70%). LCMS (APCI+) [M-Boc+H]+ 558.1; Rf: 4.41 min.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].Cl[C:23]1[N:27]([CH2:28][C:29](=[O:31])[CH3:30])[C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=2[N:24]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:23]4[N:27]([CH2:28][C:29](=[O:31])[CH3:30])[C:26]5[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=5[N:24]=4)=[CH:15][CH:14]=3)[C:5]=12
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Reactant: CC(=O)Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2ccccc21
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (1.13 g) obtained in Example 9, step C) in DMF (10 ml) was added sodium hydride (60% in oil, 0.200 g) at room temperature by small portions. After stirring for 10 min, a solution of 1-(2-chloro-1H-benzimidazol-1-yl)propan-2-one (1.25 g) in DMF (5 ml) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from methanol to give the title compound (0.371 g).
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[C:7](N)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.N([O-])=O.[Na+].[I-:17].[K+]>O>[I:17][C:7]1[CH:8]=[CH:9][C:4]2[CH2:3][CH2:2][S:1](=[O:12])(=[O:11])[C:5]=2[CH:6]=1
Reactant: [I-]
Reactant: Nc1ccc2c(c1)S(=O)(=O)CC2
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=S1(=O)CCc2ccc(I)cc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A mixture of 2,3-dihydro-1-benzothiophen-6-amine 1,1-dioxide (1.1 g) 2M hydrochloric acid (14 ml) was cooled in an ice-bath. Sodium nitrite (355 mg) in water (5 ml) was added dropwise and the mixture was stirred for 15 min before aqueous potassium iodide (830 mg) was added. The mixture was stirred overnight, before it was heated to 65° C. for 0.5 h. The mixture was cooled to 20° C. and extracted into ethyl acetate. The organic solution was washed with aqueous sodium metabisulfite solution, brine, dried and purified on two SPE silica cartridges (10 g) eluting with dichloromethane, diethyl ether and ethyl acetate. The dichloromethane fractions were combined and evaporated to give the title compound (550 mg) LCMS RT=2.65 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH3:10])[CH:4]=1)[CH3:2].[Mg+2].[Cl-].[Cl-].Cl.C[CH2:16][O:17]C(C)=O>CC#N.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:10])[C:6]([OH:9])=[C:7]([CH:8]=1)[CH:16]=[O:17])[CH3:2]
Reactant: CCc1ccc(O)c(C)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O
Product: CCc1cc(C)c(O)c(C=O)c1
Yield: 53 %

Procedure:
To a solution of the phenol of Example 150 Step 1 (5.0 g, 36.7 mmol) in 200 mL CH3CN, was added MgCl2 (5.25 g, 55.1 mmol), TEA (13.9 g, 19.2 mL, 137.6 mmol), and (CHO)N (8.3 g, 280 mmol). The reaction was heated at reflux for 3 h. After cooling, the reaction was diluted with EtOAc (500 mL) and acidified with aqueous 2N HCl until the reaction was pH 4. The reaction was diluted with 300 mL H2O. The organic layer was washed with H2O, with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (on SiO2, hexane/EtOAc=94/6) to give 3.2 g (53%) of the desired product as a clear oil.
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Cl>O.[Cu]I>[CH:6]1[CH:7]=[CH:8][C:3]([O:9][C:12]2[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:5]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccccc1Cl
Agent: [Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccccc1Oc1ccccc1
Temperature: 160 °C
Reaction time: 24 h
Yield: 56.7 %

Procedure:
85% Potassium hydroxide powders (2.18 g; 0.033 mol, 1.1 equimolar amount) were added to phenol (4.23 g; 0.045 mol, 1.5 eq.) under heating, and 1,2-dichlorobenzene (4.41 g; 0.03 mol) and copper(I) iodide (0.29 g; 0.0015 mol) were added thereto, followed by stirring at 160° C. for 24 hours. The reaction mixture was diluted with water and extracted with ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a mixture of benzene and n-hexane to give 3.48 g (yield, 56.7%) of 2-chlorodiphenyl ether as colorless crystals. m.p., 33° to 41° C.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[C:3]1=[O:13].[Br:14]Br>C(O)(=O)C>[Br:14][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[C:3](=[O:13])[N:2]([CH3:1])[CH:11]=1
Reactant: Cc1ccc2c(=O)n(C)ccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1ccc2c(=O)n(C)cc(Br)c2c1
Yield: 95.9 %

Procedure:
2,6-Dimethylisoquinolin-1-one (120.0 mg, 0.60 mmol) in acetic acid (4 mL) was treated with Br2 (96 mg, 0.6 mmol) in acetic acid (0.6 mL) at 0° C. in a manner similar to Example 72, step 2. Isolation, also in a similar manner, gave the title compound (145.0 mg, 82.9%) as a white yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.33 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 3.60 (s, 3H), 2.54 (s, 3H). LCMS: 252.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][NH2:14]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH:14][CH3:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: CN
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1cc(F)ccc1C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in acetone (20 mL) was added a 40% aqueous solution of methylamine (4.5 mL, 60 mmol) under nitrogen and the mixture stirred for 5 min. Acetone was removed in vacuo and the aqueous residue extracted with CH2Cl2. The CH2Cl2 extract was dried (Na2SO4), filtered, concentrated and the residue purified by column chromatography (SiO2, 10% ether in CH2Cl2) to provide 3.9 g (19.2 mmol, Yield 96%) of the title compound as a white solid; 1H NMR (500 MHz, CDCl3) δ ppm: 2.59 (3H, s), 2.67 (3H, d, J=5.5 Hz), 4.41 (1H, brs), 7.13-7.20 (1H, m), 7.29 (1H, dd, J=8.2, 5.5 Hz), 7.69 (1H, J=8.6, 2.1 Hz); LC/MS m/z 204 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:6](=[O:11])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:3]=1.[C:19]([CH2:22][C:23](=O)[CH3:24])(=O)[CH3:20]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[C:3]3[C:2](=[N:1][C:19]([CH3:20])=[CH:22][C:23]=3[CH3:24])[N:7]([CH:8]3[CH2:10][CH2:9]3)[C:6](=[O:11])[CH:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(-c2cccc(Cl)c2)cc(=O)n1C1CC1
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)c2c(-c3cccc(Cl)c3)cc(=O)n(C3CC3)c2n1

Procedure:
Starting compounds: 6-amino-4-(3-chlorophenyl)-1-cyclopropyl-2(1H)-pyridone and acetylacetone
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(NC(C)C)(C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 3-hydroxy-4-iodobenzoate (1 eq.) in dry THF were added trimethylsilylacetylene (5 eq.), tetrakis(triphenylphosphine)palladium (0.03 eq.), copper iodide (0.02 eq.) and diisopropylamine (2.1 eq.) under argon. The reaction mixture was stirred at 60° C. for 15 h, cooled to 20° C. and the solvents removed under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 9/1) to afford methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[Na+].S(Cl)([Cl:20])=O>CN(C)C=O>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:20])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCOc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(S(=O)(=O)Cl)cc1

Procedure:
A mixture of sodium 4-(3-methylbutoxy)benzenesulfonate (2.5 grams, 9.4 mmole), thionyl chloride (10 mL), and 5 drops of N,N-dimethylformamide was heated at reflux for 5 hours. After cooling, the excess thionyl chloride was evaporated and the residue was taken up in ethyl acetate. The solution was cooled in an ice bath and water was added. The organic phase was separated and washed with water and brine. After drying over sodium sulfate, the solvent was evaporated to afford the title compound as an oil, 2.34 grams (95%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:24][OH:25])[CH:19]=[C:20]([CH2:22][OH:23])[CH:21]=2)[CH2:13][O:12][CH2:11]1>C(#N)C>[Br:8][C:19]1[C:20]([CH2:22][OH:23])=[CH:21][C:16]([O:15][CH2:14][C:10]2([CH3:9])[CH2:13][O:12][CH2:11]2)=[CH:17][C:18]=1[CH2:24][OH:25]
Reactant: CC1(COc2cc(CO)cc(CO)c2)COC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC1(COc2cc(CO)c(Br)c(CO)c2)COC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NBS (212 mg) is added to ((5-((3-Methyloxetan-3-yl)methoxy)-1,3-phenylene)dimethanol (270 mg) in acetonitrile (5 mL) and the resulting mixture is stirred at room temperature for 3 h. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) to give the title compound. LC (method 7): tR=0.76 min; Mass spectrum (ESI−): m/z=315 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]([CH3:14])[C:4]1[N:13]=[C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([CH3:28])[C:24]=1[C:25](O)=[O:26])=[O:19])[CH3:16].CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([CH3:28])[C:24]=1[C:25](=[O:26])[NH:12][C:9]1[CH:10]=[CH:11][N:6]2[N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH3:14])[N:13]=[C:7]2[CH:8]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: CCN(C)c1nc2cc(N)ccn2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)CC)nc2c1
Yield: 90.2 %

Procedure:
A mixture of N2-ethyl-N2-methyl-[1,2,4]triazolo[1,5-a]pyridine-2,7-diamine (215 mg, 1.12 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (267 mg, 1.35 mmol), propylphosphonic anhydride (50% in ethyl acetate, 1.66 ml, 2.81 mmol) and N,N-diisopropylethylamine (574 μl, 3.37 mmol) in tetrahydrofuran (10 ml) was refluxed for 18 hours. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate 100% as eluent affording 5-[2-(ethyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (375 mg, 89.8%) as a light yellow solid. mp: 167° C., MS: m/z=372.5 (M+H+)
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH:30]1[CH:31]=[CH:32][C:33]([CH2:36][CH2:37]O)=[CH:34][CH:35]=1.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=2)[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: OCCc1ccccc1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCCc1ccccc1

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A of Example 31 after reaction with phenethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S) -cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3[(Z) 3-oxo-3-phenethoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+46 °±2.5° (c=0.5% in benzene).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40]([C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1)#[N:41]>>[C:40]([C:42]1[CH:50]=[CH:49][C:45]([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])=[CH:44][CH:43]=1)#[N:41]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(C#N)cc3)CN2C1=O
Yield: 36.9 %

Procedure:
Prepared by way of method II using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-cyanobenzoyl chloride (87 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 45 mg (37%) of 18-(4-cyanobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.0% pure (HPLC), MS m/z 696 (M−H)−, HRMS: calcd. 715.3125 and found 715.3147 (M+NH4)+, mp 164-166° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[C:10](O)(=O)[CH2:11][CH2:12][CH3:13].[H-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>O>[CH3:9][C:3]1[C:2]2[N:1]=[C:10]([CH2:11][CH2:12][CH3:13])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)c1N
Reactant: CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [H-]
Solvent: O
Product: CCCc1nc2c(C)cccc2[nH]1

Procedure:
5.00 g (41 mmol) of 2,3-diamino-toluene and 3.7 ml (41 mmol) of butyric acid are stirred in 41 ml of polyphosphoric acid at 120° C. for 3 hours, and the mixture is poured into 410 ml of water and brought to pH=9 with solid sodium hydride. Thereafter, sodium carbonate is added until the evolution of carbon dioxide has ended, the mixture is extracted five times with 100 ml of ethyl acetate each time, the combined organic phases are dried with anhydrous sodium sulphate and the solution is evaportated - finally under a high vacuum; crude weight: 5.89 g.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[S:38])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)=[S:38])=[CH:32][CH:31]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CC1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(CN2CCN(C(=S)Nc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 322 (196 mg, 0.73 mmol) was suspended in methylene chloride (10 ml), then neutralized with triethylamine (0.27 ml, 1.94 mmol). To the solution, 4-chlorophenyl isothiocyanate (140 mg, 0.83 mmol) was added followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carbothioic acid (4-chlorophenyl)amide (128 mg, yield 40%) as a light brown powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH3:18])[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:6]=2[O:5]1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:6]2[O:5][C:4]([CH2:3][CH2:2][OH:1])([CH3:18])[C:9](=[O:10])[NH:8][C:7]=2[CH:11]=1
Reactant: CC1(CCO)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [Pd]
Solvent: CO
Product: CC1(CCO)Oc2ccc(N)cc2NC1=O

Procedure:
A flask containing 2-(2-hydroxyethyl)-2-methyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (983.30 mg; 3.90 mmol; 1.00 eq.) dissolved in methanol (10.00 ml) is passed through the H-Cube using 10% Pd/C cartridge, at 1 mL per minute, in full H2 mode at 30 C. The product is afforded quantitatively upon concentration of the eluent and used directly in further reactions; LCMS: rt 0.24 min; m/z 223.06.