Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:30][CH:29]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: Nc1ccc(CN2CCCC2)cc1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1)C1CC1
Yield: 83.4 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (320 mg, 1.03 mmol) was reacted 4-(pyrrolidin-1-ylmethyl)aniline (385 mg, 1.55 mmol) to afford the desired product (387 mg, 83%) as a yellow solid: ESI MS m/z 450 [C24H24BrN3O+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1F)=O.[NH2:12][NH2:13]>CCO>[F:10][C:7]1[CH:6]=[C:5]2[C:4]([C:2]([CH3:1])=[N:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: CC(=O)c1ccc(F)cc1F
Solvent: CCO
Product: Cc1n[nH]c2cc(F)ccc12
Yield: 68.5 %

Procedure:
In a sealed flask were combined 12.99 g (83.2 mmol) 2,4-Difluoroacetophenone, 8.80 g (274 mmol, 3.3 equiv) Hydrazine and 8.7 mL EtOH and heated at 150° C. for 18 h. The resultant solid is dissolved in 150 mL EtOH, precipitated with 500 mL H2O, cooled, filtered, air and pump dried to give 8.56 g (57.0 mmol) 6-Fluoro-3-methyl-1H-indazole which is used without characterization. The material thus obtained is combined with 6.35 g (62.7 mmol, 1.1 equiv) Et3N and 1.39 g (11.4 mmol, 0.2 equiv) DMAP in 110 mL CH3CN cooled to 0° C. 14.93 g (68.4 mmol, 1.2 equiv) (BOC)2O in 80 mL CH3CN is added dropwise with stirring at 0° C. and the resultant reaction mixture stirred 2 h at 0° C. followed by 18 h at ambient temperature. The solvent is removed in vacuo and the crude material partitioned between EtOAc (200 mL) and H2O (100 mL). The pH is adjusted to 2.0 with 1N HCl, the organic phase separated, dried (MgSO4), filtered and concentrated in vacuo to an orange solid which is purified by filtration through a pad of 60 g silica gel eluted with 1.2 L DCM. The filtrate is concentrated in vacuo to give 12.68 g (50.7 mmol) of 6-Fluoro-3-methyl-indazole-1-carboxylic acid tert-butyl ester as a tan crystalline solid: 1H NMR (CDCl3, 300 MHz) δ7.78 (d, 1H, J=9.8), 7.57 (m, 1H), 7.07 (m, 1H), 2.57 (s, 3H), 1.72 (s, 9H); TLC Rf =0.52 (DCM).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[N:17]([CH3:20])[N:18]=[CH:19][C:12]=12.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[CH:4][C:3]=1[C:9]#[C:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]2[N:17]([CH3:20])[N:18]=[CH:19][C:12]=12
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc(N)cc1C#Cc1cncc2c1cnn2C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1C#Cc1cncc2c1cnn2C

Procedure:
In analogy to GP 5, 200 mg of 4-methyl-3-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-ylethynyl)-phenylamine (Intermediate 3.2, 0.4 mmol, 1 eq.) were treated with 47 μL phenyl isocyanate (0.44 mmol, 1.1 eq.) in 4 mL DCM at rt. Aqueous work-up followed by HPLC purification provided the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C)C=O.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:19])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)c(Cl)c1
Temperature: 75 °C

Procedure:
To a well stirred suspension of 5,6-dichloronicotinic acid 11 (600 g, 3.125 mole) and N,N-dimethylformamide (20.0 mL) in dichloroethane (1.2 L) was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mole). The reaction mixture was set up for heating with reflux, fitted with a gas trap filled with saturated aqueous sodium bicarbonate and heated at 75° C. until the reaction mixture formed a clear solution, about 3 h. LC/MS of a sample quenched in methanol showed only methyl ester. The reaction mixture was cooled to ambient and concentrated under reduced pressure to yield 5,6-dichloronicotinoyl chloride 12 as a thick paste.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].[CH:16](=O)[CH3:17]>CCCCCC>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]1([CH3:11])[CH2:9][O:10][CH:16]([CH3:17])[O:8][CH2:7]1
Reactant: CC(CO)(CO)OCc1ccccc1F
Reactant: CC=O
Solvent: CCCCCC
Product: CC1OCC(C)(OCc2ccccc2F)CO1

Procedure:
Using the procedure of Example 51, 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol and acetaldehyde were reacted, using hexane as solvent to give, after separation by column chromatography, t-5-(2-fluorobenzyloxy)-r-2-methyl-5-methyl-1,3-dioxane, nD25 1.4902, and c-5-(2-fluorobenzyloxy)-r-2-methyl-5-methyl-1,3-dioxane, nD25 1.4939. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[C:17]([C:28]#[N:29])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C-:30]#[N:31].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:30]#[N:31])=[C:17]([C:28]#[N:29])[C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: [C-]#N
Reactant: CCn1c2ccccc2c2cc(C=C(C#N)c3ccc(C(F)(F)F)cc3)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C(C#N)=C(C#N)c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
0.78 g (2.00 mmol) of N-ethyl-3-(2-cyano-2-(4-trifluoromethylphenyl)ethenyl) carbazole and 10 ml of N,N-dimethylformamide as solvent were placed in a 200 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.10 g (2.00 mmol) of sodium cyanide and 1.0 ml of water, which was stirred for 10 minutes. Further, 0.88 g (2.00 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 100 ml of chloroform was added. To the resultant solution was added 50 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain 0.20 g of a yellow solid. The yield of the synthesized compound was 24%, and its melting point was 180-182° C. The IR chart is shown in FIG. 17.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.[I:16]I>C1COCC1>[I:16][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a solution of 4-bromo-1,2-(methylenedioxy)benzene (5.0 g, 25.0 mmol) in THF (40 mL) cooled to −78° C. was added n-butyllithium (24 mL, 1.6 M, 37.3 mmol) and the mixture kept at −78° C. for 45 min. A solution of I2 (12.6 g, 50 mmol) in THF (40 mL) was then added. After 45 min, the reaction was allowed to warm to room temperature and quenched with water. The THF was removed and the residue treated with EtOAc (400 mL) and saturated Na2S2O3 solution (100 mL). The organic layer was dried over MgSO4 and purified by CC (silica gel, hexanes:EtOAc 1:1) to yield 4-iodo-1,2-(methylenedioxy)benzene (4.6 g, 18.5 mmol) in 74% yield: 1H NMR (CDCl3) δ 7.14-7.11 (m, 2H, Ar) 6.58(d, 1H, Ar), 5.94(s, 2H, CH2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[Br:14]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>S(=O)(=O)(O)O>[Br:14][C:12]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)c2ncccc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a flask containing 6-nitroquinoline (4 g, 23 mmol) in sulfuric acid (20 ml) was added N-bromo-succinimide (5.31 g, 29.9 mmol). The mixture was heated to 60° C. (oil bath) for 6 hours and then stored in a freezer overnight. The crude reaction mixture was poured into a beaker containing ice (250 ml). The material was basified by adding first solid sodium bicarbonate and then a saturated solution of sodium bicarbonate (to a pH of about 10). During this procedure ethyl acetate (60 ml) was also added. The material was filtered to remove insoluble material and the filtrate transferred to a reparatory funnel. Ethyl acetate (100 ml) was added and the biphasic material shaken. The organic phase was collected and shaken with an equal volume of brine solution. The ethyl acetate phase was collected and the aqueous phases were back extracted with ethyl acetate (2×100 ml). The combined organic phase was stripped to provide a solid. The solid from the above filtration was taken up in hot ethyl acetate (60 ml). The material was cooled to ambient, dried over magnesium sulfate and filtered. The solvent was stripped and the crude solid product was combined with the material obtained from aqueous work up. This material was crystallized from hot ethyl acetate/hexane to provide the desired product as a yellow powder (2.05 g).
Reaction SMILES: [Al](I)(I)I.[CH2:5]([C:8]1[CH:9]=[C:10]([O:16]C)[CH:11]=[C:12]([O:14]C)[CH:13]=1)[CH:6]=[CH2:7]>C(=S)=S>[CH2:5]([C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]([CH:9]=1)[OH:16])[CH:6]=[CH2:7]
Reactant: C=CCc1cc(OC)cc(OC)c1
Agent: I[Al](I)I
Solvent: S=C=S
Product: C=CCc1cc(O)cc(O)c1

Procedure:
The Pd-catalyzed cross-coupling reaction of 5-Bromo-1,3-dimethoxybenzene with allyl boronic acid pinacol ester produced 5-allyl-1,3-dimethoxybenzene 1 in excellent yield. AlI3 will be used for demethylating 5-Allyl-1,3-dimethoxybenzene with CS2 as solvent to produce 5-allylresorcinol 2. The bis(phosphinite) PCP ligands 3 will be obtained by diphosphorylation of 5-allylresorcinol 2 with the respective chlorophosphine and sodium hydride as a base. Iridium complexes 4 will be obtained from reaction of the respective PCP ligands 3 with [Ir(COD)Cl]2 or [Ir(COE)2Cl]2. Hydrosilylation of complexes 4 will produce the hydrosilylated complexes 5. Reaction of complexes 5 with silica gel will afford the Si2O-supported Ir complexes 6. To date, 5-allyl-1,3-dimethoxybenzene 1 has been prepared in 92% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.S(OCC)(O[CH2:16][CH3:17])(=O)=O>[OH-].[Na+]>[CH3:1][N:2]([CH3:11])[C:3]1[N:4]=[C:5]([O:10][CH2:16][CH3:17])[CH:6]=[C:7]([OH:9])[N:8]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: CN(C)c1nc(O)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(O)nc(N(C)C)n1
Reaction time: 6 h

Procedure:
155.2 g (1 mol) of 2-dimethylamino-4,6-dihydroxypyrimidine are added while stirring to 1000 cc of 1N sodium hydroxide solution 1N and the mixture is heated to 50° over a short period. 170 g (1.1 mol) of diethyl sulphate are subsequently added dropwise, over the course of 2 hours, at 40°-45°. During the dropwise addition the pH value is kept at between 7.5 and 8.0 by further addition of 1N sodium hydroxide solution. Approximately 500 cc of 1N sodium hydroxide solution are additionally required. The mixture is stirred at 40° for 6 hours, filtered off, washed with a small amount of water and dried at 90° in a high vacuum. The compound may be recrystallized from benzene. M.P. 194°-195°. The aqueous phase may be extracted with chloroform in order to obtain better yields. The chloroform solution is dried with sodium sulphate and after evaporation crystals are obtained which may be recrystallized from benzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=3)=[CH:23][C:24]=2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1cc(F)c(S(=O)(=O)Nc2nccs2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1-c1cc(-c2cccc(F)c2)ncc1Oc1cc(F)c(S(=O)(=O)Nc2nccs2)cc1Cl
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
10 mg (0.02 mmol) of 5-chloro-4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.2 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2.3 mg (10 mol %) of Pd(PPh3)4, 6.3 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 4 mg (36% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:28]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[O:33][CH2:34][CH2:35][NH2:36])[CH3:29]>O1CCCC1>[CH2:28]([O:30][C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[O:33][CH2:34][CH2:35][NH:36][C:10](=[O:12])[CH2:9][CH2:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)[CH3:29]
Reactant: CCOc1ccccc1OCCN
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccccc1OCCNC(=O)CCC(=O)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 10.4 g of 3-(4-fluorobenzoyl)propionic acid and 6.0 g of triethylamine in 120 ml of tetrahydrofuran was added dropwise 6.0 g of ethyl chloroformate at a temperature below 0° C. After stirring was continued for half an hour, to the mixture was added a solution of 9.6 g of 2-(2-ethoxyphenoxy)ethylamine in 10 ml of tetrahydrofuran. Further stirring was continued at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was concentrated to a residue under reduced pressure. The residue was recrystallized from benzene-hexane to give N-[2-(2-ethoxyphenoxy)ethyl]-3-(4-fluorobenzoyl)-propionamide melting at 98° - 100° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:32])[C:28]([F:31])([F:30])[F:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[C:26]([CH:27]([CH3:32])[C:28]([F:31])([F:29])[F:30])=[CH:25][C:24]3[O:23][CH2:22][C:21]4=[N:20][NH:19][C:18](=[O:33])[CH:17]([CH3:34])[N:16]4[C:15]=3[CH:14]=2)[CH2:11]1
Reactant: CC1C(=O)NN=C2COc3cc(C(C)C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(C(C)C(F)(F)F)c(NC4CNC4)cc3N21
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-[4-methyl-3-oxo-7-(2,2,2-trifluoro-1-methyl-ethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (0.020 g, 0.041 mmol) in DCM (3 mL) was added in TFA (0.5 mL) and the solution was stirred for 2 h. The solvent was removed in vacuo to give 9-(azetidin-3-ylamino)-1-methyl-8-(1,1,1-trifluoropropan-2-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (0.015 g, 95%). LC/MS (Table 1, Method 5) Rt=2.166 min; MS m/z: 384 [M+H]+
Reaction SMILES: C[O:2][C:3]([CH:5]([N:9]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]([N:19]=[N+]=[N-])[C:10]1=[O:22])[CH:6]([CH3:8])[CH3:7])=[O:4]>C(O)C.[Pd]>[NH2:19][C@H:11]([C:10]([NH:9][C@H:5]([C:3]([OH:4])=[O:2])[CH:6]([CH3:8])[CH3:7])=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(C(C)C)N1C(=O)C(N=[N+]=[N-])C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reaction time: 19 h
Yield: 86.5 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonyl-2-methylpropyl)-3-azido-4-phenylazetidin-2-one (500 mg.) was subjected to hydrogenolysis at 50° C. in ethanol (30 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (175 mg.). The reaction was completed in 19 hours. The same after-treatment as in Example 1 was followed to give methyl ester of phenylalanylvaline (378 mg., yield: 81.9%), which was an oil.
Reaction SMILES: C[O:2][C:3](=O)[N:4]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:8][C:7]=1[N+:23]([O-])=O)[CH3:5]>CO.O1CCCC1.[Ni]>[CH2:16]([O:15][CH2:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]2[NH:23][C:3](=[O:2])[N:4]([CH3:5])[C:6]=2[CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)N(C)c1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)[nH]c2ccc(OCCOCc3ccccc3)cc21
Yield: 97.4 %

Procedure:
To a solution of [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-methyl-carbamic acid methyl ester (0.93 g, 2.58 mmol) in methanol (50 ml) and tetrahydofuran (50 ml) was added Raney Ni and the mixture was stirred under a hydrogen atmosphere (1 atm) until all starting material was consumed as indicated by TLC. The catalyst was filtered, washed generously with tetrahydofuran, and the filtrate evaporated. The residue was washed with anhydrous tetrahydofuran and evaporated (2×15 ml). The oil was dissolved in anhydrous tetrahydofuran (30 ml) and NaH was added (0.31 g, 60%, 7.75 mmol), and the reaction mixture was heated to reflux under nitrogen for 3.5 h. The reaction was quenched with NH4Cl (sat) (20 ml), water (20 ml) and ethyl acetate (20 ml). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×25 ml). The combined organics were washed with brine (25 ml), dried over MgSO4, filtered, and evaporated to give 6-(2-benzyloxy-ethoxy)-1-methyl-1,3-dihydro-benzoimidazol-2-one (0.75 g, 97%) as a solid. Analysis calculated for C17H18N2O3 : C, 68.44; H, 6.08; N, 9.39. Found: C, 68.64; H, 6.13; N, 8.96.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][O:20][CH3:21]>>[CH3:21][O:20][CH2:19][CH2:18][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(S)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To a solution of 4-mercaptophenylboronic acid (3.08 g, 20 mmol) in anhydrous N,N-dimethylormamide (50 mL) was added solid potassium carbonate (9.7 g, 70 mmol). The mixture was stirred at 25° C. for 10 min and then treated with 1-bromo-2-methoxy-ethane (6.6 mL, 70 mmol) dropwise. The resulting mixture was stirred at 25° C. for 7 h and quenched with water. The mixture was extracted with ethyl acetate (2×150 mL), washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-(2-methoxy-ethylsulfanyl)-phenylboronic acid (4 g, 94%) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:52])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([S:24]([NH:27][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33]C)=[O:32])(=[O:26])=[O:25])=[CH:19][C:18]([S:38]([NH:41][C:42]2[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=2)[C:45]([O:47]C)=[O:46])(=[O:40])=[O:39])=[CH:17]3)(=[O:13])=[O:12])[CH:5]=1.[OH-].[Na+:54].C(O)(=O)C>C(O)C>[Na+:54].[Na+:54].[Na+:54].[C:20]1([S:24]([NH:27][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O-:33])=[O:32])(=[O:26])=[O:25])[C:21]2[C:16](=[CH:15][C:14]([S:11]([NH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([O-:52])=[O:2])(=[O:12])=[O:13])=[CH:23][CH:22]=2)[CH:17]=[C:18]([S:38]([NH:41][C:42]2[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=2)[C:45]([O-:47])=[O:46])(=[O:40])=[O:39])[CH:19]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cccc(C(=O)OC)c4)cc(S(=O)(=O)Nc4cccc(C(=O)OC)c4)cc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C([O-])c1cccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cccc(C(=O)[O-])c4)cc(S(=O)(=O)Nc4cccc(C(=O)[O-])c4)cc3c2)c1
Reaction time: 0.75 h

Procedure:
A mixture of 12.0 g of the product of Example 11 and 62.0 ml of 2N sodium hydroxide is stirred for 45 minutes. The solution is neutralized with 3.6 ml of glacial acetic acid and diluted with 400 ml of ethanol. The solvent is concentrated in vacuo to a small volume. Then it is diluted again with ethanol with the separation of an oil. The solvent is decanted off, and the oil is triturated with fresh ethanol to produce a yellow solid. The solid is separated, washed with ethanol and ether, and dried at 70° C to yield 7.3 g of the product of the Example.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17]>>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([N:14]2[CH2:20][CH2:19][CH2:18][C@H:15]2[CH2:16][OH:17])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: Nc1cccc(S(=O)(=O)N2CCC[C@H]2CO)c1

Procedure:
By subjecting 3-nitro-benzenesulfonyl chloride and L-prolinol in analogous manner to the procedure described in example B.13, the title compound was obtained. Pale-yellow oil. MS (ISP) 257.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([C:8](=[O:10])[CH3:9])=[N:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(C)c(Cl)n1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(CBr)c(Cl)n1

Procedure:
To a solution of 1-(6-chloro-5-methyl-pyridin-2-yl)-ethanone (1 eq) in CCl4 is added NBS (1 eq) and BPO (0.1 eq). The mixture is refluxed for 12 hours. After concentration, 1-(5-bromomethyl-6-chloro-pyridin-2-yl)-ethanone is isolated by flash column chromatography. MS: (ES+): 247.9 (M+1)+.