Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[CH:13]/[C:14](=[O:45])[N:15]([CH3:44])[C@@H:16]([C:28](=[O:43])[N:29]([CH3:42])[C@@H:30]([C:38](=[O:41])[NH:39][CH3:40])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH:12]=[CH:13][C:14](=[O:45])[N:15]([CH3:44])[C@@H:16]([C:28](=[O:43])[N:29]([CH3:42])[C@@H:30]([C:38](=[O:41])[NH:39][CH3:40])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C=CC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.12 h
Yield: 64.8 %

Procedure:
3-((E)-2-(Methyl((1R)-1-(methyl-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)vinyl)azetidine-1-carboxylic acid tert-butyl ester (0.45 g; 0.73 mmol) was dissolved in methylene chloride (2 mL). Trifluoroacetic acid (2 mL) was added and the reaction mixture was stirred for 7 min. Methylene chloride (50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (50 mL; pH 9) and sodium carbonate were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.29 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([C:20]4[CH:21]=[CH:22][CH:23]=[N:24][C:19]=4[O:18][C:17]([NH2:25])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.[F:37][C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1>>[F:27][C:28]1[C:33]([C:2]2[CH:3]=[C:4]3[C:15]4([C:20]5[CH:21]=[CH:22][CH:23]=[N:24][C:19]=5[O:18][C:17]([NH2:25])=[N:16]4)[C:14]4[CH:13]=[C:12]([C:42]5[CH:41]=[CH:40][N:39]=[C:38]([F:37])[CH:43]=5)[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC2(c3cc(Br)ccc3Oc3cnc(Cl)cc32)c2cccnc2O1
Reactant: OB(O)c1ccnc(F)c1
Product: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3cnc(-c4ccnc(F)c4)cc32)c2cccnc2O1

Procedure:
The titled compound was prepared by following the procedures as described in Example 18, Step 4 but using 7-bromo-3-chlorospiro[chromeno[2,3-c]pyridine-5,4′-pyrido[3,2-e][1,3]oxazin]-2′-amine, 2-fluoropyridine-3-boronic acid and 2-fluoropyridine-4-boronic acid. MS m/z=506.9 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[OH:11])=O.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19]>C(O)C>[OH:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[N:18][OH:19])[C:7]#[N:8]
Reactant: N#Cc1ccc(C=O)c(O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C=NO)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of 4-formyl-3-hydroxy-benzonitrile (CAS 84102-89-6) (6.90 g) in dry ethanol (165 ml) was added sodium acetate (4.23 g) and hydroxylamine hydrochloride (3.58 g). The mixture was stirred at r.t. for 1 h. The solvent was evaporated and the product was purified by flash chromatography (cyclohexane/EtOAc 8:2=>1:1) to give 3-hydroxy-4-(hydroxyimino-methyl)-benzonitrile (4.70 g). Light yellow solid. MS 162.0 ([M]+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1>C1C=CC=CC=1>[N:22]1([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:12]2[CH2:13][CH2:14][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(c2ccccn2)n2nnc3ccccc32)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 1.50 mL (15.7 mmol) of pyridine-2-carbaldehyde in 70 mL of benzene under an atmosphere of nitrogen was added 2.92 g (15.7 mmol) of tert-butyl 1-piperazine-carboxylate followed by 1.87 g (15.7 mmol) of 1H-benzotriazole. The reaction mixture was heated to reflux for 3 h employing a Dean-Stark® Trap. The resulting mixture was cooled to ambient temperature and all volatiles were removed in vacuo to afford the title compound (i-78).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:33]=[CH:34][C:35]=1[F:36])[O:17][C:18]1[N:23]=[C:22]2[S:24][C:25]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])=[N:26][C:21]2=[CH:20][CH:19]=1.C(N(CC)CC)C.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[C:48]([CH2:52][NH2:53])[CH:49]=[CH:50][CH:51]=1>O1CCCC1.C(OCC)(=O)C>[F:36][C:35]1[CH:34]=[CH:33][C:16]([O:17][C:18]2[N:23]=[C:22]3[S:24][C:25]([NH:27][C:28]([CH:30]4[CH2:32][CH2:31]4)=[O:29])=[N:26][C:21]3=[CH:20][CH:19]=2)=[CH:15][C:14]=1[NH:13][C:1](=[O:12])[NH:53][CH2:52][C:48]1[CH:49]=[CH:50][CH:51]=[C:46]([C:45]([F:44])([F:54])[F:55])[CH:47]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1cccc(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 143.8 %

Procedure:
To a solution of bis(trichloromethyl) carbonate (30 mg, 0.102 mmol) in tetrahydrofuran (2 mL) was added dropwise a suspension of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.290 mmol) produced in Example 16(vi) and triethylamine (80 μL, 0.580 mmol) in tetrahydrofuran (2 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. 1-[3-(Trifluoromethyl)phenyl]methanamine (50 μL, 0.348 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was diluted with ethyl acetate (20 mL), and washed successively with aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→70/30), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate (3 mL) to give the title compound (80 mg, 50%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([S:16]([Cl:15])(=[O:18])=[O:17])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc2cc(C(C)=O)oc12
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(S(=O)(=O)Cl)c2cc(C(C)=O)oc12
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2-Acetyl-7-methoxybenzofuran (5 g) (0.0263 mole) was added to chlorosulfonic acid (18.4 g) (0.158 mole) at -15° C. in portionwise (each 0.5 g) for 30 min. After stirring the reaction mixture at -10° to -5° C. for 1 hour, the resultant was gradually added dropwise to ice. The solution was extracted with ethyl acetate, washed with water and dried, followed by distilling away ethyl acetate under reduced pressure to give 5.8 g of crude 2-acetyl-4-chlorosulfonyl-7-methoxybenzofuran.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:40])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].FC(F)(F)C(O)=[O:44]>C1(C)C=CC=CC=1.C(OCC)(=O)C.CS(O)(=O)=O>[CH3:6][S:3]([OH:4])(=[O:5])=[O:44].[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:39])[CH:25]=3)[CH:17]=2)=[C:11]([CH3:40])[CH:10]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC(C)(C)C)c(F)c3)c2)c(C)c1
Reactant: O=C(O)C(F)(F)F
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a solution of tert-butyl 3-{4-[({4′-[2-(ethylsulfonyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoate (1.17 g, 2.05 mmol) in toluene (20 mL) was added trifluoroacetic acid (20 mL) under stirring at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/4) to give a colorless oil. The obtained oil was diluted with ethyl acetate, and methanesulfonic acid (0.12 mL) was added. The precipitated crystals were collected by filtration, washed and dried to give the title compound (1.00 g, yield 80%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.BrN1C(=O)CCC1=O.C(Cl)[Cl:20]>>[Cl:20][C:8]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Fc1ccc2nncn2c1
Reactant: ClCCl
Agent: O=C1CCC(=O)N1Br
Product: Fc1ccc2nnc(Cl)n2c1
Temperature: 45 °C
Yield: 63 %

Procedure:
Intermediate 14a (908 mg, 6.60 mmol) was dissolved in DCM (50 mL) and N-bromosuccinimide (1.29 g, 7.26 mmol) added. The reaction was heated to 45° C. for 4 h, then cooled and partitioned between DCM (150 mL) and saturated aqueous NaHCO3 (150 mL), and extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. Purification by FCC, using 0-5% [2M NH3 in MeOH] in DCM, gave the title compound (900 mg, 63%). LCMS (Method 1): Rt 1.94 min, m/z 216/218 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([CH3:10])=[CH:8][CH:9]=1)([O-])=O.[CH2:12]([C:14]([CH3:16])=O)[CH3:13].[H][H]>[Pt]>[CH:12]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH3:11])[CH:5]=1)([CH2:14][CH3:16])[CH3:13]
Reactant: CCC(C)=O
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1C
Agent: [Pt]
Product: CCC(C)Nc1ccc(C)c(C)c1
Yield: 100.9 %

Procedure:
A mixture of 151.2 grams (1.0 mole) 4-nitro-o-xylene, 161 grams (2.2 moles) methyl ethyl ketone, 6 grams of 5% platinum on carbon and 4.5 g of 2-nahthalenesulfonic acid monohydrate were added to a pressure vessel. Hydrogen was fed into the pressure vessel at a pressure of 20 psig. When hydrogen uptake ceased (in about 2 hours), the vessel was vented and the reaction mixture filtered. The phases were separated and the organic phase was concentrated in vacuo (at 20 mm and 70° C.) to give 178.8 g of 96.4% pure N-(sec-butyl)-3,4-xylidine in a yield of 97.2%.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47]CC5C=CC=CC=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([OH:58])([CH3:57])[CH3:56])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:55]([OH:58])([CH3:57])[CH3:56])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=1
Reactant: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.5 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 25o (100 mg, 0.12 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.07 mL, 0.63 mmol) and 10% Pd/C (20 mg, 0.02 mmol) at room temperature. The mixture was stirred under H2 at room temperature for 4 hours and filtered. The filtrate was concentrated in vacuo to give the title compound 25p as a white solid (54.8 mg, 100%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 481.0[M+HCOO]−.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1)(=O)C.[OH-].[Na+].C(O)C.C(OCC)(=O)C>O>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][NH:4][CH2:9][CH2:8][N:7]3[N:10]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: CC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCNC3)c1=O
Yield: 91 %

Procedure:
A 50 mL round bottom flask with a magnetic stirrer and reflux condenser was charged with 125g (250 mg, 0.7 mmol), aqueous NaOH (5N, 6 mL), ethanol (6 mL). The mixture stirred at reflux for 30 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a 91% yield (200 mg) of crude 125h.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:11][OH:12])[CH2:6][C:5](OC)(OC)[CH2:4]1.Cl.[OH-].Cl.[O:16]([NH2:18])[CH3:17].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>N1C=CC=CC=1.C1COCC1>[CH3:17][O:16][N:18]=[C:5]1[CH2:4][C:3]([CH2:2][O:1][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([CH2:11][O:12][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:6]1
Reactant: CON
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC1(OC)CC(CO)(CO)C1
Agent: Cl
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON=C1CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
3,3-Bis(hydroxymethyl)-1,1-dimethoxycyclobutane (1.35 g, 7.65 mmol) from Step A and 3.8 mL of 2 M aqueous hydrochloric acid solution were added to 60 mL of THF and the reaction mixture was stirred at ambient temperature for 0.5 h, under a nitrogen atmosphere. The reaction mixture was neutralized by the addition of a strongly basic hydroxide resin then filtered and concentrated in vacuo. The residue was washed with THF and dissolved in 30 mL of anhydrous pyridine. To this solution was added 767 mg (9.2 mmol) of methoxylamine hydrochloride and the resultant solution was stirred for ~20 h at ambient temperature, under a nitrogen atmosphere. t-Butyldimethylsilyl chloride (3.5 g, 23 mmol) and 60 mL of anhydrous pyridine were then added and stirring continued overnight. The bulk of the solvent was evaporated in vacuo at 35°-40° C. and the concentrate dissolved in 200 mL of methylene chloride. The methylene chloride solution was washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on a 1.5×50 cm silica gel column eluted @5 psi with 200 mL of hexane, followed by 200 mL of 2% acetone in hexane, followed by 200 mL of 3% acetone in hexane, followed by 200 mL of 4% acetone in hexane and finally 200 mL of 10% acetone in hexane, to give 583 mg (20% yield) of the title compound; MS DCI-NH3M/Z: 388 (M+H)+ ; 1H NMR (CDCl3) δ 0.04 (s, 12H), 0.87 (s, 18H), 2.61 (d, 4H), 3.58 (s, 4H), 3.82 (s, 3H).
Reaction SMILES: C([Li])CCC.[OH:6][C:7]([C@H:10]1[C@@H:13]([CH2:14][CH:15]=[CH2:16])[N:12]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:11]1=[O:25])([CH3:9])[CH3:8].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(O)(=O)C>O1CCCC1>[CH3:23][C:22]([CH3:24])=[C:17]([N:12]1[C@H:13]([CH2:14][CH:15]=[CH2:16])[C@H:10]([C:7]([CH3:9])([O:6][C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])[CH3:8])[C:11]1=[O:25])[C:18]([O:20][CH3:21])=[O:19]
Reactant: C=CC[C@@H]1[C@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC[C@@H]1[C@H](C(C)(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A solution of n-butyl lithium (0.46 ml of 1.38 M solution in hexane) was added to a solution of methyl 2-[(3R, 4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (150 mg) in tetrahydrofuran (3 ml) at -70° C. and the mixture was stirred for 15 minutes at -70° C. A solution of p-nitrobenzyl chloroformate (161 mg) in tetrahydrofuran (3.2 ml) was added to the reaction mixture at -70° C. and the mixture was stirred for 10 minutes at -70° C. The mixture was allowed to warm to 0° C. during 30 minutes and stirred at 0° C. for 1.5 hours. Acetic acid (0.043 ml) was added to the mixture at 0° C. and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed with brine, aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (10:1-3:1) to give methyl 3-methyl-2-[(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate (123 mg) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[N-:21]=[N+:22]=[N-:23].[Na+].CCOC(C)=O>CN(C=O)C>[N:21]([C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9])=[N+:22]=[N-:23]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N=[N+]=[N-]
Temperature: 60 °C
Yield: 96 %

Procedure:
A mixture of 8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (80 mg, 0.25 mmol, prepared according to Example 23, Step 12.2) and sodium azide (81 mg, 1.24 mmol) in DMF (1 mL) was stirred and heated at 60° C. for 3 h. The reaction mixture was cooled to RT, poured into AcOEt and washed successively with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to yield the crude title compound (77.4 mg, 0.24 mmol, 95%) as a brownish solid, which was used in the next step without further purification. MS: 329 [M+1]+; HPLC: AtRet=2.56.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[CH:9]=[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]2=[O:25].C([Sn]([C:41]#[C:42][Si:43]([CH3:46])([CH3:45])[CH3:44])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:10]1[C:11]2[C:6](=[CH:5][C:4]([F:26])=[C:3]([F:27])[C:2]=2[C:41]#[C:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:7](=[O:25])[C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Yield: 69 %

Procedure:
6.7 g of ethyl 8-bromo-1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Example Z20), 10.8 g of tributylstannyl-trimethylsilyl-acetylene and 0.87 g of tetrakis(triphenylphosphine)-palladium(0) are refluxed for 24 hours in 50 ml of absolute toluene under a nitrogen atmosphere. The product crystallises from the reaction mixture at -18° C. 4.8 g of ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate are obtained (69% of theory).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:8]([S:14](Cl)(=[O:16])=[O:15])([S:10](Cl)(=[O:12])=[O:11])[CH3:9].C(S(Cl)(=O)=O)S(Cl)(=O)=O.C(N(CC)CC)C.C(O)(O)CCCC.C(S(Cl)(=O)=O)CS(Cl)(=O)=O>C(COC)OC>[CH:8]1([S:14](=[O:16])(=[O:15])[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][S:10]1(=[O:12])=[O:11])[CH3:9]
Reactant: OCCCCCO
Reactant: CC(S(=O)(=O)Cl)S(=O)(=O)Cl
Agent: CCCCC(O)O
Agent: O=S(=O)(Cl)CCS(=O)(=O)Cl
Agent: O=S(=O)(Cl)CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC1S(=O)(=O)OCCCCCOS1(=O)=O
Reaction time: 0.75 h

Procedure:
1,5-Pentanediol (4.17 g, 0.04 mole) was dissolved in 350 ml of glyme in a 1 liter round bottom flask and the solution brought to -20° C. 1,1-ethanedisulfonyl chloride, synthesized in the same manner as the methanedisulfonyl chloride, (Example I) was dissolved in 25 ml of glyme and this solution added dropwise to the solution in the flask. Triethylamine (8.08 g, 0.08 mole) was dissolved in 125 ml of glyme and this solution was added to the pentanediol/ ethanedisulfonyl chloride solution over a 1 hour period. After the additions were completed, the mixture was brought to 25° C. over a 45 minute period in a water bath. The mixture was roto-evaporated under reduced pressure, at a temperature below 35° C. The residue was washed three times with 20 ml of 5% sodium bicarbonate the resulting emulsion being separated by centrifugation. Water was decanted from the final oil wash, and methylene chloride was added. This solvent apparently dissolved all or most of the impurities, leaving the product suspended in the solution. The product was obtained by vacuum filtering the solution through Whatman #5 qualitative filter papers.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.[F-].[K+].C(Cl)Cl>CN(C=O)C>[NH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=3)=[CH:11][C:6]=2[N:7]=1
Reactant: Nc1nc2cc(Br)ccc2o1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(N)nc3c2)CC1
Temperature: 90 °C
Reaction time: 12 h
Yield: 44.7 %

Procedure:
5-Bromobenzo[d]oxazol-2-amine (824 mg, 3.9 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (1.8 g, 5.8 mmol), Potassium fluoride (674 mg, 11.61 mmol) were dissolved in DMF under N2 atmosphere. This mixture was purged with N2 for 30 mins Pd(dppf)2Cl2.CH2Cl2 (252 mg, 0.3 mmol) was added to the above mixture and again purged with N2 for 30 mins. The reaction mixture was stirred at 90° C. for 12 h. Work up (EtOAc/H2O) followed by column purification on combiflash using a gradient mixture of EtOAc and Petether (1:1) as eluent afforded the titled compound (550 mg) as an off-white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.38-7.36 (m, 2H), 7.26-7.22 (m, 2H), 7.02 (d, J 7.9, 1H), 6.05 (s, 1H), 4.01-3.90 (m, 2H), 3.49-3.55 (m, 2H), 2.50-2.40 (m, 2H), 1.50 (s, 9H).