Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH:27]=O)=[CH:21]2)[CH3:13].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:27][C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[CH:19][C:18]([CH2:17][CH2:16][CH2:15][N:14]([CH2:29][CH3:30])[CH2:12][CH3:13])=[CH:26][CH:25]=2
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4ccc(Br)cc43)cc2c1
Temperature: 95 °C
Yield: 60.5 %

Procedure:
A mixture of 5-bromo-2-oxindole (41 mg, 0.19 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 52 mg (59%) of the title compound as a red-orange solid.
Reaction SMILES: [Na].Br[C:3]1[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:7](=[O:29])[N:6]([CH3:30])[C:5]=2[N:4]=1.Cl.[CH:32]([OH:35])([CH3:34])[CH3:33]>O>[OH:21][CH2:20][CH2:19][CH2:18][N:8]1[C:9](=[O:17])[C:10]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]([O:35][CH:32]([CH3:34])[CH3:33])=[N:4][C:5]=2[N:6]([CH3:30])[C:7]1=[O:29]
Reactant: CC(C)CCn1c(Br)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: CC(C)O
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(C)CCn1c(OC(C)C)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sodium (0.12 g, 5.15 mmol) was dissolved in isopropanol (8 mL) and 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.03 mmol, intermediate 82) was added. The reaction was stirred at room temperature for 15 h. The reaction was treated with 6N HCl to achieve pH=1, and stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with DCM (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to leave a golden oil. The oil was purified using two 2000 micron preparative TLC plate eluted with 50% ethyl acetate/hexanes to give 1-(3-hydroxypropyl)-7-isopentyl-8-isopropoxy-3-methyl-1H-purine-2,6(3H,7H)-dione (0.27 g, 75 yield) as a white solid. LCMS retention time=3.325 min and 97% purity, LCMS MH+=353. 1H NMR (CDCl3) δ 5.20-5.30 (m, 1H), 4.17 (t, 2H, J=8 Hz), 4.07 (t, 2H, J=8 Hz), 3.73 (t, 1H, J=8 Hz), 3.45-3.54 (m, 5H), 1.85-1.93 (m, 2H), 1.58-1.66 (m, 2H), 1.48-1.57 (m, 1H), 1.42 (d, 6H, J=8 Hz), 0.94 (d, 6H, J=8 Hz).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[C:12]([C:11]1[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: CN1CCNCC1
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1COCCO1
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C#N)CC1

Procedure:
0.5 g of the product from Example 1 and 0.48 g of N-methylpiperazine are boiled in 8 ml of dioxane for 3 hours. The mixture is then concentrated in vacuo, water is added to the residue and the solution formed is rendered neutral. The solid which has precipitated out is isolated, washed and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1([Cl:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:3]1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)C1C=CC=CC1(Cl)Cl

Procedure:
To a cold (5° C.) mixture of 55.0 g (0.423 mole) of ethyl acetoacetate, 70 ml. of benzene, 18.3 ml. of 33% sodium hydroxide, and 141 ml. of water was added simultaneously with vigorous stirring 80.0 g (0.457 mole) of o-chlorobenzoyl chloride and 76 ml. of 33% sodium hydroxide in 1 hour. The aqueous solution of the sodium salt of ethyl o-chlorobenzoylacetoacetate was stirred with 22.5 g (0.424 mole) of ammonium chloride for 18 hours. The aqueous solution was then saturated with 25.0 g of sodium chloride. At this moment, some precipitate formed which was filtered. The analysis indicated this material was mainly the sodium salt of ethyl o-chlorobenzoylacetoacetate. The sodium salt and the aqueous filtrate were combined and acidified with dilute hydrochloric acid. The oil which separated was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was Kugelrohr distilled to give 30.0 g of oil which contained mainly ethyl o-chlorobenzoylacetoacetate. This material was stirred with a mixture of 7.2 g of ammonium chloride, 14 ml. of concentrated ammonium hydroxide and 150 ml. of water and worked up as described in Example 4 to give 16.6 g (15% ) of crude ethyl o-chlorobenzoylacetate which was about 92% pure. A mixture of 15.0 g. (0.065 mole) of ethyl o-chlorobenzoylacetate, 9.5 (0.070 mole) of sulfuryl chloride and 20 ml. of chloroform was held at reflux for 6 hours and concentrated to give 17.3 g of crude ethyl 2-chloro-o-chlorobenzoylacetate. A mixture of 17.0 g (0.065 mole) of ethyl 2-chloro-o-chlorobenzoylacetate, 4.94 g (0.065 mole) of thiourea and 65 ml. of ethanol was held at reflux for 2 hours and worked up as described in Example 4 to give 15.0 g of solid, m.p. 114°-136° C. which was recrystallized twice from ethanol to give 5.8 g (31%) of ethyl 2-amino-4-(o-chlorophenyl)- 5-thiazolecarboxylate, m.p. 165°-166° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C-]#[N:19]>>[C:11]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)([CH3:9])[CH3:10])#[N:19]
Reactant: [C-]#N
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CC(C)(C#N)c1ccc(O)cc1

Procedure:
A preferred manner of practicing this invention constitutes heating a solventless mixture of Bisphenol A and cyanide ion in a closed vessel to about 185° C. and maintaining that temperature for about 20 hours to produce 4-(1-cyano-1-methylethyl)phenol. Preferred conversions and yields based on Bisphenol A are about 100 percent and 80 percent respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>CN(C)C=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:21][CH2:20][N:8]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:9]1=[O:16]
Reactant: BrCCOC1CCCCO1
Reactant: Cc1ccc2c(c1)C1(CCNCC1)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C1(CCNCC1)C(=O)N2CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Methyl-spiro[indoline-3,4′-piperidin]-2-one (prepared as in Org. Prep. Proced. Int. (1995), 27(6), 691-694)(0.05 g, 0.023 mmol) was dissolved in dry N,N-dimethylformamide (4.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 10.0 mg, 0.28 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C. 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.048 g, 0.023 mmol). The reaction mixture was stirred at 0° C. for 1 hour, then at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was then partitioned between water-ice and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a crude oil. The crude oil was purified via flash chromatography (3% methanol/dichloromethane) to yield the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH2:19][CH3:20])=[C:16]([S:21][C:22]([F:25])([F:24])[F:23])[C:15]([C:26]#[N:27])=[N:14]1.S(=O)(=O)(O)[OH:29]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH2:19][CH3:20])=[C:16]([S:21][C:22]([F:25])([F:23])[F:24])[C:15]([C:26]([NH2:27])=[O:29])=[N:14]1
Reactant: O=S(=O)(O)O
Reactant: CCOc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Product: CCOc1c(SC(F)(F)F)c(C(N)=O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Yield: 73 %

Procedure:
A stirred mixture of 1-(2,6-dichloro-4-trifluoromethylpheny)-5-ethoxy-4-trifluoromethylthio-1 H-pyrazole-3-carbonitrile (0.55 g, 1.22 mmol) and concentrated sulfuric acid (0.55 ml) was heated at 100° C. for 3 hours. The cooled mixture was added to ice water and the precipitate filtered off, washed with water and air-dried. The crude product was dissolved in heptanes/ethyl acetate (1:1) and filtered. The filtrate was evaporated to give the title compound (0.42 g, yield 73%) as yellowish crystals, mp 161° C., 1H NMR (CDCl3): 1.32 (t, 3H, CH3), 4.68 (q, 2H, OCH2), 5.54 and 6.69 (bs, 2H, C(O)NH2), and 7.77 (s, 2H, Ar—H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.Br[CH2:16][CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[K+]>C(O)C>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][CH2:2][NH:1][CH2:16][CH:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:11])[NH2:12]
Reactant: OC(CBr)c1ccccc1
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1cc(OCCNCC(O)c2ccccc2)ccc1O

Procedure:
A suspension of 21.9 g of 5-(2-aminoethoxy)-salicylamide, 36.0 g of α-(bromomethyl)-benzyl alcohol and 30 g of potassium bicarbonate in 240 ml of ethanol is refluxed for 15 hours, with stirring. The reaction mixture is then cooled and filtered and the filtrate is evaporated. The evaporation residue is partitioned between 300 ml of ethyl acetate and 100 ml of water and the organic phase is separated off, dried over magnesium sulfate and evaporated. The residue is dissolved hot in as little ethanol as possible and made to crystallise, yielding α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)ethyl]-aminomethyl]-benzyl alcohol with a melting point of 174°-175° (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[NH3:11]>C1COCC1>[NH2:11][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][CH3:10])[N:5]=1
Reactant: N
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: C1CCOC1
Product: CSc1nc(N)cc(Cl)n1

Procedure:
Compound 6 was prepared from commercially available 4,6-dichloro-2-(methylthio)pyrimidine followed scheme 4. To prepare compound 6.1,4,6-Dichloro-2-(methylthio)pyrimidine was reacted with ammonia in THF in a sealed tube to provide 4-Amino-6-chloro-2-(methylthio)pyrimidine in good yield. Amino group of the resulting compound was protected with suitable protecting group such as BOC to afford compound 6.1. Compound 6.1 was then reacted with methyl 4-hydroxybenzoate in the presence of base to provide the amine protected intermediate, 2 which upon deprotection under acidic condition to afford methyl 4-(6-amino-2-(methylthio)pyrimidin-4-yloxy)benzoate (3). Reaction of compound 3 with hydrazine hydrate in methanol provided 4-(6-amino-2-(methylthio)pyrimidin-4-yloxy)benzohydrazide (6.4) in good yield. The hydrazide was then reacted with S-methyl N-[3-(trifluoromethyl-phenyl)thiourea in the presence of base to yield compound 6.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1Br
Product: O=C(Cl)c1ccccc1Br
Yield: 100 %

Procedure:
1.5 g (0.00745 mol) of 2-bromobenzoic acid were dissolved in 25 ml of thionyl chloride under argon and boiled under reflux for 2 hrs. The excess thionyl chloride was distilled off and the residue was taken up twice with 50 ml of toluene and concentrated each time. 1.63 g (100%) of 2-bromobenzoyl chloride were obtained as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH3:2].N([O-])=[O:12].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([C:3]1[C:4](=[O:12])[NH:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C)nc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
A solution of 3-ethyl-6-methyl(pyridin-2-yl)amine (also see Reimlinger, H. et al. Chem. Ber., 109, 118-124 (1976); Sawyer, J. R. H.; Wibberley, D. G. J. Chem. Soc (Perkin 1), 113801143 (1973); Childs, R. F.; Johnson, A. W. Chem. Ind. (London), 542 (1964)) (41.2 g, 0.4 mol) in sulfuric acid (817 mL) is chilled in an ice bath. To this solution is added a solution of sodium nitrite (23.81 g, 0.345 mol) in H2O (200 mL). The resulting mixture is stirred at ambient temperature for 20 hr. The mixture is brought to pH 9.0 by addition of 3N sodium hydroxide (370 mL) and extracted with ethyl acetate (9×200 mL). The combined organic extract is washed with brine (300 mL), dried, filtered and concentrated. The residue is crystallized from heptane (300 mL) to afford 3-ethyl-6-methyl-1H-pyridin-2-one (also disclosed by Mistryukov, E. A. et al. Izv. Akad. Nauk SSR 512-519 (1964); Chem. Abstr. 64, 90713) (35.78 g, 87% yield) as a white, crystalline solid. The resulting product exhibited characteristic 1H NMR spectrum consistent with that reported in the literature.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([F:27])([F:26])[F:25])[CH2:19]1.C1COCC1>[Pd].CO>[F:30][C:2]([F:1])([F:29])[CH2:3][CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([F:27])([F:26])[F:25])[CH2:19]1
Reactant: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(N2CCCC(C(F)(F)F)C2)c(C(=O)NCCC(F)(F)F)cc1N
Reaction time: 8 h

Procedure:
A mixture of N-(3,3,3-trifluoro-propyl)-2-[3-trifluoromethyl-piperidinyl]-4-methylamino-5-nitro-benzoic acid amide (100 mg, 0.22 mmol), Pd/C (10 mg), THF (5 mL) and MeOH (15 mL) is stirred under 3 bar H2-atmosphere overnight. The mixture is filtered, and the filtrate is concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(C)c1CCl
Reactant: CCOC(=O)Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxy-4-methylphenyl)acetate (Step C, 1.84 g, 9.5 mmol), K2CO3 (1.96 g, 14.2 mmol) in DMF (10 ml) was added 2,6-Dimethylbenzyl chloride (1.61 g, 10.4 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours at the room temperature, diluted with ethyl acetate and washed with water (2×), and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 4:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[NH:14][C:13]2=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:25](I)[CH2:26][CH3:27]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=3)[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(C)cc3c2=O)CC1
Reactant: CCCI
Product: CCCn1c(=O)n(C2CCN(C(=O)OCC)CC2)c(=O)c2cc(C)ccc21
Yield: 97 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 1.0 g (3.02 mmol) of 3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline (Compound f) was used in place of Compound 24 and propyl iodide was used in place of methyl iodide, whereby 1.09 g (yield: 97%) of Compound c was obtained as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:8]1[CH:9]=[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])[C:3]([C:4]#[N:5])=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1ccc(F)cc1Br
Product: N#Cc1ccc(F)cc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-4-fluorobenzonitrile was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 7 part c) to give 5,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.25-7.33 (2H, m), 7.40-7.44 (1H, m), 7.86 (1H, dd, J 9 and 6), 8.35-8.42 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[N:9]O)[CH2:7][O:8][C:4]=2[CH:3]=1.[H][H]>O1CCCC1.CO.[Ni]>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]([NH2:9])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: ON=C1COc2cc(F)ccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: NC1COc2cc(F)ccc21
Yield: 33.7 %

Procedure:
A mixture of the above described 6-fluoro-benzofuran-3-one oxime (5.38 g, 32 mmol; HPLC 1.489 min) and Raney-Nickel (2.4 g) in tetrahydrofuran (125 mL) and methanol (125 mL) was hydrogenated at 100 bar hydrogen-pressure at 50° C. for 18 h. Filtered the catalyst off, washed with methanol and tetrahydrofuran, all volatiles very removed in vacuum to give the crude product which was purified by Si—NH2 column chromatography with n-heptane/ethyl acetate to give the title compound as a light brown liquid (1.65 g, 34%, HPLC 0.367 min 100%), MS (ISP) m/e=154.0 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:33])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C)C=O>[C:13]([O:12][C:11]([N:10]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)[CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:33])=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(O)cc2)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a solution of tert-butyl (2R)-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2-(4′-hydroxy-1,1′-biphenyl-4-yl)ethyl]carbamate (240 mg) and potassium carbonate (78 mg) in N,N-dimethylformamide (4 ml) was added tert-butyl bromoacetate (110 mg), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give tert-butyl [[4′-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-yl]oxy]acetate (245 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([O:14][CH3:15])=[O:13])[CH2:3][CH2:2]1.[O:16]=[C:17]1[N:23]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C@@H:33]([C:46](O)=[O:47])[CH2:34][C:35]3[CH:44]=[C:43]([CH3:45])[C:38]4[NH:39][C:40](=[O:42])[O:41][C:37]=4[CH:36]=3)=[O:31])[CH2:26][CH2:25]2)[CH2:22][CH2:21][C:20]2[CH:49]=[CH:50][CH:51]=[CH:52][C:19]=2[NH:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:16]=[C:17]1[N:23]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C@H:33]([CH2:34][C:35]3[CH:44]=[C:43]([CH3:45])[C:38]4[NH:39][C:40](=[O:42])[O:41][C:37]=4[CH:36]=3)[C:46]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH2:11][CH2:10][CH2:9][C@H:8]4[C:12]([O:14][CH3:15])=[O:13])[CH2:5][CH2:6]3)=[O:47])=[O:31])[CH2:28][CH2:29]2)[CH2:22][CH2:21][C:20]2[CH:49]=[CH:50][CH:51]=[CH:52][C:19]=2[NH:18]1
Reactant: COC(=O)[C@@H]1CCCN1C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(C)c3[nH]c(=O)oc3c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
93 mg (0.44 mmol) methyl (S)-1-piperidin-4-yl-pyrrolidine-2-carboxylate were added to a solution of 200 mg (0.39 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 140 mg (0.44 mmol) TBTU and 61 μL (0.44 mmol) triethylamine in 2 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were concentrated by evaporation and lyophilised.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([SiH2:17][O:18][C:19]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:20]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:21]=1[S:22][C:23]1[C:24]([CH2:40]O)=[CH:25][CH:26]=[CH:27][C:28]=1[N:29]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:16])([CH3:15])[CH3:14].[C:54]1(=[O:64])[NH:58][C:57](=[O:59])[C:56]2=[CH:60][CH:61]=[CH:62][CH:63]=[C:55]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([SiH2:17][O:18][C:19]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:20]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:21]=1[S:22][C:23]1[C:24]([CH2:40][N:58]3[C:54](=[O:64])[C:55]4[C:56](=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:57]3=[O:59])=[CH:25][CH:26]=[CH:27][C:28]=1[N:29]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:14])([CH3:15])[CH3:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCCN1c2cccc(CO)c2Sc2c1cccc2C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCN1c2cccc(CN3C(=O)c4ccccc4C3=O)c2Sc2c1cccc2C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
0.68 ml (4.36 mmol) of diethyl azodicarboxylate was slowly added dropwise under argon and while cooling with ice to a solution of 1.95 g (3.35 mmol) of [6-(tert-butyl-diphenyl-silanyloxymethyl)-10-hexyl-phenothiazin-4-yl]-methanol, 876 mg (5.03 mmol) of phthalimide and 968 mg (3.69 mmol) of triphenylphosphine in 25 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for 2 hours and at room temperature for 20 minutes and then worked up analogously to that described in Example 2.1.1 ea. The residue was chromatographed on 250 g of silica gel with diethyl ether/hexane (1:3), whereupon, after precipitation from hexane, 1.74 g (73.1%) of 2-[6-(tert-butyl-diphenyl-silanyloxymethyl)-10-hexyl-phenothiazin-4-ylmethyl]-2,3-dihydro-1H-isoindole-1,3-dione were obtained as a light yellowish amorphous solid. MS: 710 (M+, 100), 653(61), 506(16), 370(36), 308(41), 268(40), 224(21), 160(34), 130(45), 43(43).