Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:9])=[O:8].[N+:18]([C:21]1[C:22]([S:27]Cl)=[N:23][CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:14]([O:13][C:11]([NH:10][C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:27][C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:7]([OH:9])=[O:8])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1cccnc1SCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
(S)-6-Amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk86) (270 mg, 1.096 mmol) was added to a solution of nitro-2-pyridinesulfenyl chloride (313 mg, 1.644 mmol) in dichloromethane (30 ml), and triethylamine (1.53 ml, 10.96 mmol) was added dropwise to the suspension over 3 minutes. The reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure using an evaporator, and the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoic acid (Compound tk87) (62 mg, 14%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>O>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([OH:8])=[O:7])[CH3:13]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(CC(=O)O)OCC
Temperature: 100 °C
Yield: 96.1 %

Procedure:
To a 250 mL round-bottomed flask with magnetic stirring that contained ethyl 3,3-diethoxypropanoate (20.0 g, 102.0 mmol, colourless oil, 97%), a previously prepared solution of NaOH (5.23 g, 131.0 mmol) in H2O (30 mL) was added. The resulting mixture was stirred to reflux (100° C.) during 1 h. After allowing it to temper, the mixture was acidified using HCl 37% and it was extracted with AcOEt, 8×20 mL. The resulting organic phase was washed with 1×20 mL NaCl sat., dried with Na2SO4, filtered and concentrated to dryness. The obtained oil was confirmed to correspond to the title compound (15.9 g, 98.0 mmol, 96%).
Reaction SMILES: [CH:1]1([C:5]2[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19]([NH:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[N:10]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccnc(C2CCC2)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccnc(C2CCC2)n1

Procedure:
This compound was obtained according to example 2, step B] from 2-cyclobutyl-pyrimidin-4-ylamine (0.15 g), and 3-chloro-2-methyl-benzenesulfonyl chloride (0.27 g) as a light brown solid (47 mg). MS (ESI): 338.1 (MH+).
Reaction SMILES: [BH4-].[Na+].[I-].[NH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N+:9]([CH3:15])=[CH:10]2>CO.O>[NH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([CH3:15])[CH2:10]2
Reactant: C[n+]1ccc2c(N)cccc2c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCc2c(N)cccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
Sodium borohydride (17.8 g, 0.47 mol) was added portionwise over 2 h to an ice cold solution of 5-amino-2-methylisoquinolinium iodide (18.8 g, 65 mmol) in methanol (1.5 L) and water (60 ml). The mixture was then stirred at 25° C. for 18 h. and concentrated in vacuo. The residue was extracted into water and dichloromethane. The organic layer was dried (Na2SO4) and concentration in vacuo gave the title compound (8.87 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([O:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Oc3ccccc3)nc12
Temperature: 100 °C
Reaction time: 13 h
Yield: 62.7 %

Procedure:
A mixture of 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.051 g, 0.12 mmol), phenol (0.017 g, 0.18 mmol), potassium phosphate (0.056 g, 0.26 mmol), 2-di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl (0.0041 g, 0.012 mmol) and Pd(OAc)2 (0.002 g, 0.009 mmol) in 1 mL of toluene was stirred at 100° C. for 13 h, then at 150° C. for 4 h. The resulting dark orange mixture was partitioned between 10 mL of ethyl acetate and 10 mL of water. The organic layer was dried over MgSO4, filtered and concentrated to an orange oil. Column chromatography (0-20% EtOAc/hexanes) afforded 0.032 g (62%) of impure 2,2-dimethyl-1-[2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a yellow oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15].C(OCC)(=O)C.CCCCCC>C(O)C.O.Cl.C(OCC)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]
Reactant: CC(C)=CCOc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CC(C)=CCOc1cc(N)ccc1Cl

Procedure:
To a refluxing well-stirred suspension of iron powder (19.6 g, 100 mesh) in ethanol (60 mL), water (13.4 mL) and 36% hydrochloric acid (1.4 mL) was added 1-chloro-2-(3-methyl-2-butenyloxy)-4-nitrobenzene (24 g) in portions over 15-30 minutes. After 3 hours thin-layer chromotography (TLC) (ethyl acetate:hexane, 40:60) showed no substrate. The reaction mixture was then filtered hot and the iron oxide filter cake was washed with hot ethanol. The combined ethanol washes were evaporated to produce a residue. The residue was taken up in diethyl ether, washed with aqueous bicarbonate and water, dried (MgSO4), filtered, and evaporated, to give 4-chloro-3-(3-methyl-2-butenyloxy)benzenamine, 19.8 g of light brown oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:26]Br>>[CH3:32][O:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:30]=1)[CH2:26][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(OC)cc(OC)c2)c(=O)[nH]c1=O
Yield: 50.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (212 mg, yield: 50.2%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[F:12][C:13]([F:21])([F:20])[C:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:11][C:3]1[C:2]([NH2:1])=[C:9]([Cl:10])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:17]([C:14]1([C:13]([F:21])([F:20])[F:12])[CH2:16][CH2:15]1)=[O:18]
Reactant: NCc1ccc(Cl)c(N)c1Cl
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Nc1c(Cl)ccc(CNC(=O)C2(C(F)(F)F)CC2)c1Cl

Procedure:
The sub-title compound is prepared from 3-amino-2,4-dichloro-benzylamine (0.310 g, 1.01 mmol), 1-trifluoromethyl-cyclopropane carboxylic acid (0.17 g, 1.1 mmol), TBTU (0.39 g, 1.2 mmol) and TEA (0.71 mL) in DMF in analogy to step 1 d.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].[Br:11][C:12]1[S:16][C:15]([C:17](Cl)=[O:18])=[CH:14][CH:13]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH:6][C:17]([C:15]1[S:16][C:12]([Br:11])=[CH:13][CH:14]=1)=[O:18]
Reactant: NCc1cc(F)cc(F)c1
Reactant: O=C(Cl)c1ccc(Br)s1
Solvent: ClCCl
Product: O=C(NCc1cc(F)cc(F)c1)c1ccc(Br)s1
Reaction time: 2.5 h
Yield: 90.5 %

Procedure:
Thionyl chloride (35 ml) is added dropwise to 5-bromo-2-thiophenecarboxylic acid (4.92 g, 23.77 mmol) at 0° C., and the mixture is then heated at 90° C. overnight. After the mixture has cooled to room temperature, the solvent is removed in vacuo, and the residue is washed with cold heptane. 5-Bromothiophene-2-carbonyl chloride is obtained as an almost white solid. 3,5-Difluorobenzylamine (209 mg, 1.46 mmol) is added to a mixture of 5-bromothiophene-2-carbonyl chloride (300 mg, 1.33 mmol), piperidinomethylpolystyrene (410 mg, 3.5 mmol/g, 1.44 mmol) in anhydrous dichloromethane (5 mL) and stirred for 2.5 hr. The reaction mixture is diluted with dichloromethane and filtered through silica gel. The filtrate is concentrated to afford 5-bromo-thiophene-2-carboxylic acid 3,5-difluoro-benzylamide as a white solid (400 mg, 90% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[CH2:6])[CH3:2].CO[CH2:14][N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:5]1([O:7][CH2:8][CH:9]=[CH2:10])[CH2:6][CH2:14][N:15]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16]1)=[O:11])[CH3:2]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=CCOC(=C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC1(C(=O)OCC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the 2-allyloxy-acrylic acid ethyl ester (431 mg) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (847 μl) in dichloromethane (10 ml) was added at 0° C. trifluoroacetic acid (21 μl). The resulting solution was warmed to room temperature and stirred overnight. The crude product was purified by column chromatography on silica gel, eluted with a solution of ethyl acetate in hexanes (25-100%) to give the title compound (341 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[C:5]([CH3:12])=[N:4]1)[CH3:2].[OH-].[NH4+:14].O>O1CCCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([S:8]([NH2:14])(=[O:10])=[O:9])[C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: CCn1cc(S(=O)(=O)Cl)c(C)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(S(N)(=O)=O)c(C)n1
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 1-ethyl-3-methyl-1H-pyrazole-4-sulfonylchloride (0.154 g, 0.73 mmol, Matrix Scientific) in tetrahydrofuran (10 mL) was added dropwise an aqueous solution of 30% ammonium hydroxide (0.20 mL, 1.7 mmol). The reaction mixture was stirred for 1 hour, water (2 mL) was added, and the solvent was concentrated under reduced pressure to precipitate a solid. The solid was isolated by filtration, rinsed with water, and dried to afford 41 mg of the title compound. 1H NMR (CDCl3) δ 7.80 (s, 1H), 4.75 (br s, 1H), 4.11 (q, 2H), 2.44 (s, 3H), 1.49 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cnn2Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cnn2Cc2ccccc2)n1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
A reaction vial was charged with 1-benzyl-5-chloro-1H-pyrazolo[4,3-b]pyridine (0.210 g, 0.862 mmol) (Peak 1 from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (0.22 g, 0.96 mmol, Aldrich), cesium carbonate (0.281 g, 0.862 mmol, Aldrich) and toluene (2 mL, 20 mmol). Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.068 g, 0.086 mmol, Aldrich) was added and the mixture was degassed by a stream of nitrogen through the solution for 15 minutes. The reaction vial was sealed and heated to 110° C. for 2 hours, then was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and water and the aqueous was extracted with two further portions of EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded product (0.19 g, 50%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4](Cl)=[N:3]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[I-].[Na+]>Cl>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:3]1
Reactant: C1CCNC1
Reactant: CN(C)Cc1cccc(OCCCNc2nc(Cl)nn2C)c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: CN(C)Cc1cccc(OCCCNc2nc(N3CCCC3)nn2C)c1
Yield: 61 %

Procedure:
A mixture of 1-methyl-3-chloro-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-5-amine (0.4 g), pyrrolidine (0.71 g) and sodium iodide (0.3 g) was heated at 180° in an autoclave for 16 hr. The reaction mixture was dissolved in dilute hydrochloric acid, washed with ethyl acetate, basified with sodium hydroxide and extracted with toluene. The toluene extracts were fractionally distilled to give the title compound as a pale yellow oil (0.27 g) b.p. 210° (0.04 mm). TLC silica; ethyl acetate:isopropanol: water:0.88 ammonia 25:15:8:2; Rf 0.6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH2:15]([SH:17])[CH3:16].CCN(C(C)C)C(C)C>>[CH2:15]([S:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])[CH3:16]
Reactant: CCS
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 39a was used, starting from 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c), ethanethiol and DIEA to give 4-ethylsulfanyl-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 341 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:7]([O:9]CC)=[O:8]>C(O)C>[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:14][CH2:15][CH2:16][O:17]1)[CH3:13])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)C1(C)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
1 N Aqueous sodium hydroxide (130 ml) was added to a solution of ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer, 25.7 g) in ethanol (150 ml), and stirred at ambient temperature overnight. The resultant solution was concentrated under reduced pressure. The residue was dissolved in a saturated aqueous solution of sodium chloride (80 ml) and washed with diethyl ether. Diethyl ether (100 ml) was added to the aqueous solution, adjusted to pH 1 with 10% hydrochloric acid and the diethyl ether layer was separated. The aqueous layer was extracted with diethyl ether (50 ml) twice. The diethyl ether layer and the extracts were combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After evaporating the solvent, the residue was crystallized and washed with n-hexane. The precipitates were collected by filtration and dried to give 2-methoxyimino-3,3-ethylenedioxybutyric acid (syn isomer, 17.7 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[C:23]([CH2:29][OH:30])[CH:22]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][OH:20].C(N(CC)CC)C>ClCCl.ClCCl.CS(C)=O>[C:21]1([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:13]([CH:12]=[O:11])[CH:14]=2)[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[C:23]([CH:29]=[O:30])[CH:22]=1
Reactant: OCc1ccc(-c2ccc(CO)c(CO)c2)cc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc(-c2ccc(C=O)c(C=O)c2)cc1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 26 %

Procedure:
To a solution of oxalyl chloride 2M in dichloromethane (DCM) (2.8 mL, 5.6 mmol, 4.4 molar equivalents) cooled to −78° C. is added dropwise a solution of dimethylsulfoxyde (DMSO) (0.8 mL, 11.1 mmol, 8.8 molar equivalents) in DCM (10 ml). The solution is stirred at −78° C. for 5 min and 3,3′,4,4′-tetra(hydroxymethyl)-1,1′-biphenyl 1c (0.22 g, 1.3 mmol, 1.0 molar equivalent) dissolved in a mixture of DCM-DMSO (1 ml-2 ml) is added dropwise. The solution is stirred for 1 h at −78° C. and triethylamine (6 mL) is slowly added at −78° C. The reaction mixture is stirred 10 minutes at −78° C. and slowly warmed up to room temperature. Ice-cold water (30 ml) is added to the reaction mixture and the aqueous layer extracted with DCM (3×30 ml). The organic fractions are combined, dried over magnesium sulfate, filtered and concentrated in vacuum to give a brown oil. Purification by column chromatography on silica gel (eluent: hexane-ethyl acetate 6/4) gave the title compound as an off-white powder (90 mg, 42%). 1H NMR (300.13 MHz, CDCl3) δ (ppm) 8.02 (dd, J1=8.1, J2=1.8 Hz, 2H) 8.14 (d, J=8.1 Hz, 2H) 8.28 (d, J=1.8 Hz, 2H) 10.58 (s, 2H) 10.68 (s, 2H).
Reaction SMILES: [CH:1]1([C:8]([O:10]CC)=[O:9])[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C1(C(OCC)=O)C2(CCCCC2)C1>>[CH:1]1([C:8]([OH:10])=[O:9])[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: CCOC(=O)C1CC12CCCC2
Agent: CCOC(=O)C1CC12CCCCC2
Product: O=C(O)C1CC12CCCC2

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 12A for the product from Example 1A.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Si:10]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:31]2[CH:30]=[CH:29][C:28]([O:27][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)[Si](Oc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Reactant: Fc1cc(Br)cnc1Br
Product: CC(C)(C)[Si](Oc1ccc(-c2ncc(Br)cc2F)cc1)(c1ccccc1)c1ccccc1

Procedure:
2,5-dibromo-3-fluoropyridine and 4-tert-butyldiphenylsilyloxybenzeneboronic acid are reacted analogously to Example 1 to give 5-bromo-2-(4-tert-butyldiphenylsilyloxyphenyl)-3-fluoropyridine. ##STR31##
Reaction SMILES: C([N:8]1[CH2:16][CH2:15][CH:14]2[N:17]([C:18](=[O:21])[CH2:19][CH3:20])[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[C:18]([N:17]1[CH:14]2[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:9][NH:8][CH2:16][CH2:15]2)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)N1C2CCCC1CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1C2CCCC1CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution in dichloromethane (7 ml) of 3-BOC-10-propionyl-3,10-diazabicy-clo[4.3.1]decane obtained in Example 13 (0.32 g), cooled at 0° C., trifluoroacetic acid (0.83 ml) in 3 ml of dichloromethane, is added. The mixture is kept under stirring at room temperature for 3 hours. The solvent is then evaporated and the residue treated with an aqueous solution of saturated NaHCO3, then extracted with CH2Cl2. The organic phase is separated, anhydrified on sodium sulphate and evaporated. 0.21 g of a light oil corresponding to the compound 10-propionyl-3,10-diazabicyclo[4.3.1]decane (14a) are obtained.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3].C(NC1C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1)(=O)C.N12CCCN=C1CCCCC2.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:4][C:5](=[O:15])[C:6](=[N+:29]=[N-:30])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CCOC(=O)Cc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C=CCOC(=O)C(=[N+]=[N-])c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
(3,4-Difluoro-phenyl)acetic acid allyl ester (64 g) was dissolved in acetonitrile (400 mL) and 4-acetamidobenzenesulfonyl azide (p-ABSA, 87 g, 0.36 mol) was added and the mixture stirred at room temperature for 15 min. The mixture was then cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 58.6 mL) was added dropwise at 0° C. during 30 min. The mixture was allowed to warm up to rt (room temperature) and stirred at rt for 4-20 h (until TLC showed completion of reaction). Saturated ammonium chloride (500 mL) was added and the organic phase was separated from the water phase. The water phase was extracted with diethylether (3×200 mL) and the four combined organic phases were dried (Magnesium sulphate) and evaporated in vacuo. The resulting solid was extracted with a 50:50 mixture of diethylether/pentane (3×200 mL). The combined ether phases were evaporated in vacuo (keep temperature below 40°) and purified by flash column chromatography (silicagel, eluent: 10:90 mixture of diethylether/pentane). The yellow fractions were combined and evaporated in vacuo (keep temperature below 40°) to give 70 g diazo-(3,4-Difluoro-phenyl)acetic acid allyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=1)[N:6]=[CH:5]2.[C:21](=[NH:35])(SCC1C=CC2C(=CC=CC=2)C=1)[CH3:22]>C(O)C>[O:18]1[C:15]2[CH:16]=[CH:17][C:12]([C:7]3[N:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:21](=[NH:35])[CH3:22])[CH:3]=4)[N:8]=3)=[CH:13][C:14]=2[O:20][CH2:19]1
Reactant: CC(=N)SCc1ccc2ccccc2c1
Reactant: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Solvent: CCO
Product: CC(=N)Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
A suspension in ethanol (80 ml) of 6-amino-2-(3,4-methylendi-oxy-phenyl)-quinazoline (5 g, 0.019 mol) and S-2-naphthylmethyl thioacetimidate bromidrate (5.63 g, 0.019 mol, prepared as described in Tetrahedron Letters 38, 179-182 (1997), was stirred at r.t. for 24 hrs. Then S-2-naphthylmethyl thioacetimidate bromidrate (2.8 g, 0.010 mol) was added and the mixture was stirred at r.t. for further 24 hrs., then was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was basified with Na2CO3 and extracted with ethyl acetate. The product was extracted with aqueous HCl (0.001 N) for three times. The aqueous layers were collected, basified with Na2CO3 and extracted with ethyl acetate. The organic layer was washed with water and dried over Na2SO4, concentrated under reduced pressure, and then the residue was triturated with diethyl ether. The yellow solid was filtered and dried in vacuum to give the titled product (2.4 g, 42% yield).