Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.ClCCl.CN(C=O)C.[CH3:19][S:20]([C:23]1[S:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21].[CH3:31][C:32]([CH3:53])([CH3:52])[CH2:33][CH2:34][NH:35][C:36](=[O:51])[C@H:37]([CH3:50])[CH2:38][C@H:39]([OH:49])[C@@H:40]([NH2:48])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.ClCCl>[CH2:41]([C@H:40]([NH:48][C:28]([C:26]1[S:27][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:24][CH:25]=1)=[O:30])[C@@H:39]([OH:49])[CH2:38][C@H:37]([C:36](=[O:51])[NH:35][CH2:34][CH2:33][C:32]([CH3:31])([CH3:52])[CH3:53])[CH3:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(S(C)(=O)=O)s1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
N-Cyclohexylcarbodiimide-N′-methyl polystyrene (138 mg @ 1.70 mmol/g; ex. Novabiochem) was treated with dichloromethane (0.5 ml) followed by a solution of 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in 4:1 dichloromethane/DMF (0.5 ml). 5-Methanesulfonyl thiophene-2-carboxylic acid (50 mg, 0.23 mmol) in DMF (0.5 ml) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenyl-hexanoic acid (3,3-dimethylbutyl)-amide (D2) (50 mg, 0.16 mmol) in dichloromethane (0.5 ml) were then added and the mixture was stirred gently overnight at room temperature. It was then diluted with dichloromethane (1 ml) and treated with methylisocyanate polystyrene (150 mg @ 1.80 mmol/g; ex. Novabiochem) and tris-(2-aminoethyl)-amine polystyrene (150 mg @ 3.20 mmol/g; ex. Novabiochem), and the mixture was stirred gently for a further 2 h. It was then filtered and the spent resins were washed with DMF (1 ml) and dichloromethane (1 ml). The combined filtrates were evaporated to dryness and the residue was triturated with diethyl ether to afford the title compound as a white solid (57 mg, 72%).
Reaction SMILES: C1(S[C:8]2([O:11][C:12]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:13]=3[CH:14]=[O:15])[CH2:10][CH2:9]2)C=CC=CC=1.[C-]1C2C(=CC=CC=2)C=CC=1.[Li+].O>C1COCC1>[CH:8]1([O:11][C:12]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][C:13]=2[CH:14]=[O:15])[CH2:10][CH2:9]1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 6 %

Procedure:
Freshly cut lithium metal (97 mg, 13.9 mmol) was added to a solution of naphthalene (1.77 g, 13.9 mmol) in THF (20 mL) and the mixture was sonicated at room temperature for 30 min. to produce a dark green solution of lithium naphthalenide. A solution of 2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)benzaldehyde (Description 1, 96 mg, 0.27 mmol) in THF (2 mL) was cooled to −78° C. and the solution of lithium naphthalenide in THF (2 mL) was added dropwise until the intense green colour persisted. The reaction was then stirred for 5 min., water (6 mL) was added and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (80:20), to give to give the title compound as a colourless oil (4 mg, 6%). 1H NMR (360 MHz, CDCl3)δ0.86 (4H, m), 3.82-3.9 (1H, m), 7.42 (2H, m), 7.62 (1H, d, J 2.5 Hz), and 10.36 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH2:25])=[O:5])[CH3:2].[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH:35]=O)=[CH:28][CH:27]=1.S([O-])([O-])(=O)=O.[Mg+2].[Na]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:35][CH2:34][CH2:33][CH2:32][C:29]1[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=1)=[O:5])[CH3:2]
Reactant: O=CCCCc1ccncc1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na]
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Temperature: -10 °C
Yield: 50.3 %

Procedure:
To a dry flask were added 5.0 g (14.9 mmol) of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester, 1.98 g (13.5 mmol) of 4-(pyridin-4-yl)butyraldehyde (diluted with 0.5 mL of CDCl3), 8.12 g (67.7 mmol) of anhydrous magnesium sulfate, and a magnetic stirring bar. The flask was purged with nitrogen, cooled to -10° C., and stirred as 11.5 mL of dry CDCl3 was introduced gradually by syringe. The mixture was stirred under nitrogen for about 20 minutes. Next, the septum was removed, and 670 mg (17.6 mmol) of sodium borohyrdide was added rapidly. The septum was immediately replaced, and the system was again purged with nitrogen. The mixture was stirred under nitrogen at about -5° C. as 10 mL of dry methanol was added gradually by syringe. After a few minutes at this temperature, the reaction was removed from the cooling bath and partitioned between 80 mL of ethyl acetate and 100 mL of water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with a gradient of 4-9% methanol in methylene chloride; repeated using 5-15% methanol in methylene chloride) to give the title compound (3.19 g). 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB--NH3 /CI): m/e=470.4 (M+H). An additional 1.91 g of less pure material was also isolated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.Cl.[NH2:15][OH:16]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1
Reactant: O=C1CCN(CCCCCO)CC1
Reactant: NO
Agent: Cl
Product: OCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Hydroxypentyl)-4-piperidone oxime is prepared from 1-(5-hydroxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C([Li])CCC.[Cl:18]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:18][C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=1
Reactant: Cn1cnc(-c2ccccc2)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole (0.600 g, 3.79 mmol) in 15 mL THF at −78° C. under nitrogen was added n-butyllithium 2.5 M in hexanes (1.67 ml, 4.17 mmol) dropwise over 3 min. The resulting orange-brown solution was allowed to stir for 30 min, at which time a solution of hexachloroethane (0.988 g, 4.17 mmol) in 5 mL THF was added slowly down the side of the flask. The orange-brown solution was allowed to stir for 1 h, and was quenched with sat'd aq. NH4Cl, warmed to ambient temperature, and stirred overnight. The mixture was extracted with EtOAc, the organic layers collected and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-chloro-1-methyl-4-phenyl-1H-imidazole as a brown solid. MS m/z=193 [M+H]+. Calc'd for C10H9N2Cl: 192.6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Br:20][C:12]1[S:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:14][CH:13]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)NCc1nccs1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ncc(Br)s1

Procedure:
A solution (2 L) of 1.33 kg of 2-t-butoxy carbonylaminomethylthiazole in ethyl acetate was added to an aqueous solution (20 L) of 8.6 kg of sodium acetate, and the mixture was stirred. Bromine (1.35 L) was added dropwise to this solution (internal temperature: 19 to 24° C.) over a period of 3.5 hr, and the mixture was stirred at an internal temperature of 25.5±5° C. for 14 hr. Sodium sulfite pentahydrate (180 g) was added thereto, the mixture was then extracted with 3 L of ethyl acetate, and the organic layer was washed with 1 L of water and 1.53 L of a 6 M aqueous sodium hydroxide solution. The aqueous layer was then extracted with 3 L of ethyl acetate. The organic layers were combined, were dried over anhydrous magnesium sulfate, and were filtered. The solvent was removed from the filtrate by evaporation under the reduced pressure, followed by substitution concentration twice with 2 L of ethanol to give 944 g of 5-bromo-2-t-butoxy carbonylaminomethylthiazole.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([CH3:16])([CH3:15])[C:10](=[O:14])[CH2:11][C:12]#[N:13].[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CC(C)(O)C#N>ClCCl>[Cl:17][C:18]1[CH:26]=[C:25]([S:27][CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](=[O:21])[CH:11]([C:12]#[N:13])[C:10](=[O:14])[C:9]([CH3:16])([CH3:15])[CH3:8]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CSc1ccc(C(=O)Cl)c(Cl)c1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C#N)C(=O)C(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
Triethylamine (1.78 g) was added to a stirred solution of 4,4-dimethyl-3-oxopentanenitrile (2.0 g) in dichloromethane and the mixture was stirred at room temperature for 2 hours. A solution of 2-chloro-4-methylsulphenylbenzoyl chloride (3.02 g) in dichloromethane was added and the mixture stirred at room temperature overnight. Acetone cyanohydrin (1.36 g) was added and the mixture stirred for 4 days, then filtered. The filtrate was washed with hydrochloric acid (2M), water, aqueous sodium bicarbonate solution, water, then dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography (hexane, ethyl acetate and acetic acid). The main fraction was washed with aqueous sodium hydroxide (2M), water, dried and evaporated to dryness to give 1-(2-chloro-4-methylsulphenylphenyl)-2-cyano-4,4-dimethylpentan-1,3-dione (COMPOUND 664, 0.16 g) as a white solid, m.p. 97°-99° C.
Reaction SMILES: [K].O[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7].C(O)C.O.[NH2:15][NH2:16]>O>[C:6]([C:5]1[CH:4]=[CH:3][NH:16][N:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)C=CO
Reactant: NN
Agent: [K]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc[nH]n1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
Under nitrogen atmosphere, mixture of 50.00 g of pinacolone and 42.00 g of methyl formate was cooled to 0° C., and then 56.00 g of potassium t-butoxide was added to the mixture over the period for 3 hours. During that, the temperature of the mixture was kept below 20° C. After that, the reaction mixture was stirred at 30° C. for 5 hours. Diethyl ether was added to the reaction mixture which was cooled to room temperature, as a result, solid was produced. The solid was collected by filtration, and dried under reduced pressure to give 32.12 g of 1-hydroxy-4,4-dimethyl-1-pentene-3-one potassium salt. 21.61 g of 1-hydroxy-4,4-dimethyl-1-pentene-3-one potassium salt was suspended to 150 ml of ethanol. 6.52 g of hydrazine hydrate was added to the suspension, and then refluxed for 7 hours. 50 ml of water was added to the reaction mixture which was cooled to room temperature, and the mixture was concentrated to 40 ml under reduced pressure. The concentrated solution was extracted by ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 6.83 g of 3-t-butyl-1H-pyrazole.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]([CH3:16])([CH3:15])[CH2:9]OS(C)(=O)=O)([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[K+].O>CS(C)=O>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]([CH3:16])([CH3:15])[CH2:9][C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(CC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Yield: 57.6 %

Procedure:
To the solution of methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl ester (5 g, 16.8 mmol) in anhydrous dimethyl sulfoxide (50 mL) was added KCN (2.85 g, 44 mmol). The reaction mixture was heated at 120° C. for 16 h. The mixture was cooled, and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4) to give 4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butyronitrile as a yellow oil (2.2 g, 57%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([F:29])[CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[C:22]([F:29])[CH:21]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1F
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4F)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (66 mg, 75%), MS (ISP) m/z=354.5 [(M+H)+], mp 270° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][S:2]SC.[CH:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH:10]=[CH:9][CH:8]=[C:7]3[CH:6]=1>N1C=CC=CC=1>[CH3:1][S:2][C:6]1[C:7]2=[C:16]3[C:11](=[CH:10][CH:9]=[CH:8]2)[CH:12]=[CH:13][CH:14]=[C:15]3[CH:5]=1
Reactant: CSSC
Reactant: C1=Cc2cccc3cccc1c23
Solvent: c1ccncc1
Product: CSC1=Cc2cccc3cccc1c23
Yield: 76 %

Procedure:
As an example of the benefits that can be realized by use of the two-step procedure, controlled potential electrolysis of dimethyl disulfide in the presence of acenaphthylene in the absence of an organic nucleophilic base resulted in copious polymer formation. But when the same electrolysis procedure was conducted in the additional presence of pyridine, an oxidation-resistant adduct of this invention formed which on eliminative aromatization in the second step resulted in the production of 1-methylthioacenaphthylene in 76% yield using electrochemical reductive elimination.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][NH:25][S:24]4(=[O:30])=[O:29])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:31]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:31])[S:24]4(=[O:29])=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCNS4(=O)=O)cc3)CC2)c(C)c1
Reactant: CI
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCN(C)S4(=O)=O)cc3)CC2)c(C)c1

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl][4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-2-yl)phenyl]methanone (150 mg) described in Example 271 and methyl iodide (24 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (103 mg) was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[H][H]>CCOC(C)=O.[Pd]>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:1]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)CCCc1ccc2cccnc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCc1ccc2c(n1)NCCC2

Procedure:
A solution of 19-3 (2.3 g, 9.4 mmol) in 50 mL EtOAc was treated with 10% Pd/C (230 mg) and a hydrogen balloon. After 4 d the reaction filtered through celite, concentrated, and purified by flash chromatography (silica, 70% EtOAc/hexane), providing 19-4 as a yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([CH:35](O)[CH3:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([CH:35]([O:23][C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:11]([CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:10]=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=2)[N:18]=4)[CH3:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol (300 mg, 0.96 mmol), 3-(1-hydroxyethyl)azetidine-1-carboxylic acid tert-butyl ester (213 mg, 1.06 mmol) and PPh3 (379 mg, 1.46 mmol) in dioxane (5 mL) was added DIAD (285 μL, 1.46 mmol) and the resulting yellow solution stirred at RT for 2 h. Further 3-(1-hydroxyethyl)azetidine-1-carboxylic acid tert-butyl ester (105 mg, 0.53 mmol), PPh3 (190 mg, 0.73 mmol) and DIAD (143 μL, 0.73 mmol) were added and the resulting mixture stirred for 2 h. The reaction mixture was partitioned between EtOAc and 1M NaOH, the organic phase dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) affording 3-{1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}azetidine-1-carboxylic acid tert-butyl ester (312 mg, 66%). LCMS: RT 3.76 min [M+H]+ 495.2
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])[OH:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:30][O:31][C:32](=[O:50])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:36]=1)=[CH2:34]>C(Cl)Cl>[CH3:30][O:31][C:32](=[O:50])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:36]=1)[CH2:34][P:4]([CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOP(O)C(NC(=O)OCc1ccccc1)C(C)C
Reactant: C=C(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 1-(benzyloxycarbonylamino)-2-methylpropyl-phosphonous acid ethyl ester (6.2 g 20.7 mmol) in 150 ml CH2Cl2 was added DIEA (6.5 mL, 47.5 mmol). The mixture solution was cooled down to 0° C. over an ice-water bath. TMSCI (5.5 mL, 42.0 mmol) was added dropwise under N2. The reaction mixture was stirred at ambient temperature for 2 hours, then cooled to 0° C. again. A solution of 2-(3-(t-butoxycarbonylamino)methylphenyl)-propenoic acid methyl ester (6.7 g, 23.0 mmol) in 15 mL CH2Cl2 was added to the reaction mixture. The resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction was quenched by 10 mL MeOH, then concentrated in vacuo, and the residue was taken up into 300 mL ethyl acetate. The organic phase was washed with 2 N NaHSO4, water, and brine. The solvent was evaporated in vacuo, and the crude product was purified by flash chromatography on silica gel to afford 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(ethoxy)phosphinoyl)propanoic acid methyl ester (10.7 g, 18.1 mmol, 81%) as white solid.
Reaction SMILES: Br[CH2:2][C:3]([C@H:5]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:12][CH:11]=2)[C:7](=[O:25])[CH2:6]1)=O.[C:26]([NH2:29])(=[S:28])[CH3:27]>O1CCCC1>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([N:8]2[CH2:9][C@H:5]([C:3]3[N:29]=[C:26]([CH3:27])[S:28][CH:2]=3)[CH2:6][C:7]2=[O:25])=[CH:15][CH:14]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Solvent: C1CCOC1
Product: Cc1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)cs1
Temperature: 40 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
(R)-4-(2-Bromo-acetyl)-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (0.040 g, 0.098 mmol) was dissolved in tetrahydrofuran (1 ml) and thioacetamide (0.007 g, 0.098 mmol) was added and the mixture was stirred at 40° C. for 24 hours. The tetrahydrofuran was evaporated and the residue was purified by column chromatography on silica gel using at first a 1:1-mixture then a 4:1-mixture of ethyl acetate and hexane as the eluent to yield the title compound as a light yellow solid (0.030 g, 80% of theory). MS (m/e)=383.3 (M+H)+.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[C:16]([S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:17]=1>CN(C=O)C>[C:22]([NH:21][S:18]([C:16]1[CH:17]=[C:12]([NH:11][CH:1]=[O:3])[CH:13]=[CH:14][C:15]=1[S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])(=[O:19])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCS(=O)(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=CO
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CCS(=O)(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.82 ml of formic acid is added dropwise to 1.85 ml of acetic anhydride. After the mixture has been stirred at 50° C. for 2 hours, a solution of 2.5 g of 5-amino-N-tert-butyl-2-ethylsulfonylbenzenesulfonamide in 10 ml of DMF is added dropwise at room temperature. This mixture is first stirred at 50° C. for 3 hours and then concentrated under a high vacuum. The residue is taken up in water and the mixture is extracted with ethyl acetate. After the organic phase been dried over magnesium sulfate, the solvent is distilled off. The residue (3.0 g) contains the desired product and is of adequate purity for further reactions.