Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.C[C:5]1([CH3:13])[O:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])O1.CN(C1C=CC=CN=1)C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])C(Cl)=O>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]([C:7](=[O:12])[CH2:8][C:9]([O:10][CH2:5][CH3:13])=[O:11])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
To a dichloromethane solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10 g) and dimethylaminopyridine (17 g), a dichloromethane solution of 3-methyl-4-nitro-benzoyl chloride (14 g) was added dropwise under ice cooling. After stirring at room temperature for 3 hours and then adding 100 ml of ethanol, the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off under the reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain ethyl 3-(3-methyl-4-nitro-phenyl)-3-oxo-propionate (12.4 g). mp; 207-211° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:11][O:12][C:7]=2[C:6]=1[O:23][CH3:24].Cl[CH2:26][C:27]([OH:29])=[O:28]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:26][C:27]([OH:29])=[O:28])=[CH:17][CH:18]=3)=[CH:11][O:12][C:7]=2[C:6]=1[O:23][CH3:24]
Reactant: O=C(O)CCl
Reactant: COc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)c(-c3ccc(OCC(=O)O)cc3)coc2c1OC

Procedure:
NaH is dissolved in dry dimethylformamide under nitrogen atmosphere at 0°. 7,8-Dimethoxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one [cp. J. Inst. Chem. (Calcutta) 43, 234 (1971)], dissolved in dry dimethylformamide, is added slowly, then a solution of chloroacetic acid. The solution is heated at 70° for 5 h and evaporated under vacuum to about one third of its original volume. After cooling, water is added and a precipitate occurs which is filtered and crystallized in methanol to give 7,8-dimethoxy-3-(4-carboxymethoxyphenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:16]([NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: Nc1cccnc1Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Nc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
N2-phenylpyridine-2,3-diamine (14.1 g, 76 mmol) and acetone (8.39 mL, 114 mmol) was added to a solution of acetic acid and dichloromethane. Sodium triacetoxyborohydride (22.59 g, 107 mmol) was added to the reaction mixture and stirred overnight at room temperature. Reaction mixture was quenched with 1N HCl. Organic layer was extracted with ethyl acetate. Ethyl acetate solution was washed with 1N sodium hydroxide solution followed by brine and dried over anhd. MgSO4. N3-isopropyl-N2-phenylpyridine-2,3-diamine (16.3 g, 94% yield) was isolated from crude by column chromatography using hexanes and ethyl acetate as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[Na+]>C(O)C.O>[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
A mixture of 14.9 g. of ethyl p-aminobenzoate, 50 ml. of hexamethylphosphoramide, 10.1 g. of 8-phenyloctyl chloride and 6.75 g. of sodium iodide is stirred and heated in an oil bath at 110° C. for 24 hours. The mixture is chilled, diluted with 50 ml. of water and 25 ml. of ethanol, chilled and filtered. The solid is washed with ethanol-water (1:1) and with water to give crystals, m.p. 61°-68° C. Recrystallization from ethanol gives white crystals, m.p. 75°-76° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[N:10]([CH2:12][C:13](=[O:24])[N:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=1)[CH3:15])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:25])[N:10]([CH2:12][C:13](=[O:24])[N:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][CH3:28])=[CH:18][CH:17]=1)[CH3:15])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CN(CC(=O)N(C)c1ccc(CO)cc1)C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(N(C)C(=O)CN(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Under argon to 1.23 g (3.6 mmol) [[(4-Hydroxymethyl-phenyl)-methyl-carbamoyl]-methyl]-methyl-carbamic acid benzyl ester in 40 ml DMF were added 580 mg (13.3 mmol, 3.7 eq, 55% disp) sodium hydride, followed by 3.8 ml (59.6 mmol, 16.6 eq) methyl iodide. The suspension was stirred at RT over night, and added to ice water. The layers were separated and the inorganic one was extracted with 50 ml CH2Cl2 (3×). The combined organic layers were washed with water (2×), dried over MgSO4, filtered and evaporated. Column chromatography on silica gel with a gradient of CH2Cl2/MeOH (100:0-98:2) afforded 0.984 g (77%) [[(4-Methoxymethyl-phenyl)-methyl-carbamoyl]-methyl]-methyl-carbamic acid benzyl ester as a light yellow oil (Rf 0.07 CH2Cl2:MeOH 9:1), MS: 356 (M), +), which was deprotected according to 6.1. to give N-(4-Methoxymethyl-phenyl)-N-methyl-2-methylamino-acetamide as yellow oil (Rf 0.2 CH2Cl2:MeOH 9:1), MS: 223 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[N:8]([C@@H:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6](=[O:7])[C:5]2=[CH:24][CH:25]=1.Cl>C(O)C.[Zn]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:24][CH:25]=1)[C:6](=[O:7])[N:8]([C@@H:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9]2
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc(N)cc2C1=O
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1Cc2cc(N)ccc2C1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of diethyl (S)-2-(4-aminophthalimido)glutarate (10.5 g, 30.2 mmol) in ethanol (150 ml) was cooled in an acetonitrile/CO2 bath. Concentrated HCl (25 ml) was added followed by 30 mesh granular Zn (10.5 g, 0.161 mole) (Fisher) when the internal temperature has reached −40° C. The reaction mixure was stirred 1.5 hours at this temperature and a further 1 hour at −10° C. The excess of Zn was filtered from the solution, 10% palladium on carbon (1.0 g) was added, and the solution shaken under hydrogen at (30-50 psi) overnight. The catalyst was removed by filtration through celite and the filtrate concentrated in vacuo. The residue was absorbed onto silica gel (15 g) and purified by chromatography on silica gel (440 g) eluting with ethyl acetate:methylene chloride (1:14 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[N-:21]=[N+]=[N-].[Na+]>C(#N)C.C1COCC1.C(OCC)(=O)C>[NH2:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1OCCCCCCCCCCCBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccccc1OCCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound 22 (0.506 g) was dissolved in 50 ml of acetonitrile. Sodium azide (0.395 g) was then added to that, and 29-hour reaction was carried out by refluxing, followed by 95-hour reaction at room temperature. After the resultant was cooled down to room temperature, the solid components were removed by filtration. The solvent of the filtrate was then distilled away under reduced pressure, and 0.313 g of a transparent, viscous liquid was obtained. This liquid was dissolved in 15 ml of THF distilled from calcium hydride in a nitrogen atmosphere, and was cooled in an ice bath. Lithium aluminum hydride (0.054 g) was then dissolved in 20 ml of dried THF, and was dripped. After the resultant was stirred in an ice bath for one hour, 80 μl of ion-exchange water, 80 of 15 wt % of aqueous potassium hydride solution, and 240 μl of ion-exchange water were added so as to stop the reaction. The precipitate generated was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. The solid obtained was then dissolved in ethyl acetate (30 ml), and was washed twice with 30 ml of ion-exchange water. The organic phase was then collected, and was dehydrated with magnesium sulfate. The desiccant agent was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. In this manner, 0.2 g of (11-aminoundecyl)tolylether 23, which was a white solid, was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>ClCCl>[CH3:1][O:2][C:3](=[O:9])[CH2:4][S:5]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:7])=[O:6]
Reactant: C1COCCN1
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To chlorosulfonyl-acetic acid methyl ester (3.39 g, 19.6 mmol) in dichloromethane (50 mL) is added morpholine (8.6 mL, 98 mmol). The resulting mixture is stirred at rt during 2 h and the solvent is evaporated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([CH3:15])=[N:13][NH:12][C:11](=O)[C:10]=2[C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[N:12]=[N:13][C:14]([CH3:15])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)c(Cl)c1
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1.75 g of 5-(3,4-dichlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 6 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure to obtain 1.80 g of 3-chloro-5-(3,4-dichlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxiii) of the present invention).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][Cl:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[ClH:12].[CH2:2]([NH:9][CH2:10][CH2:11][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: ClCCNCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: c1ccc(CNCCNc2ccccc2)cc1

Procedure:
A solution of 13 (8.618 g, 42.0 mmol) and aniline (11.75 g, 126 mmol) in toluene (40 niL) was heated to 130° C. (1.5 h). The mixture was triturated with dichloromethane (200 mL) and filtered. Recrystallization from ethanol (220 mL) afforded the title compound 14 as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].[NH4+].[Cl-]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCCl
Product: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Reaction time: 12 h
Yield: 110.2 %

Procedure:
To a stirred solution of 4-bromophenol (25.1 g, 146 mmol), and imidazole (19.9 g, 292 mmol) in 1,2-dichloroethane (150 mL) at 23° C. was added triisopropylsilylchloride (34.4 mL, 161 mmol). The mixture was stirred for 12 h and poured onto saturated aqueous NH4Cl (400 mL), followed by extraction with CH2Cl2 (3×200 mL). The combined extracts were washed with brine (300 mL), dried (Na2SO4), and concentrated in vacuo to give a pale yellow oil which was crude oil was purified via short-path distillation (0.5 mmHg, 130° C.) to yield (4-Bromo-phenoxy)-triisopropylsilane as a colorless oil (53.0 g, 99% yield). Rf 0.81 (3:1 hexanes/EtOAc) IR (thin film) 2945, 2892, 2867 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.30 (2H, d, J=9 Hz), 6.75 (2H, d, J=9 Hz), 1.29-1.18 (3H, m), 1.08 (18H, d, J=7 Hz). 13C NMR (75 MHz, CDCl3) δ 155.0, 132.0, 121.5, 112.9, 17.6, 12.4. HRMS calcd. for C15H26OSiBr (MH+) 329.0936. found 329.0937.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:24]([F:25])=[C:23]([F:26])[C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:27])[C:16]=2[F:28])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CO.O1CCOCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:28])=[C:17]([F:27])[C:18]([C:19]([OH:21])=[O:20])=[C:23]([F:26])[C:24]=2[F:25])[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(F)c(F)c(C2(NC(=O)OCc3ccccc3)CC2)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NC1(c2c(F)c(F)c(C(=O)O)c(F)c2F)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
In a mixture of 14 ml of methanol and 14 ml of dioxane was dissolved 1.8 g of methyl 4-(1-benzyloxycarbonylaminocyclopropyl)-2,3,5,6-tetrafluorobenzoate. To the resulting solution was added 14 ml of a 1N aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 50 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid, and 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and n-hexane was added to the residue obtained. The resulting crystals were collected by filtration to obtain 1.7 g (yield: 97.7%) of 4-(1-benzyloxycarbonylaminocyclopropyl)-2,3,5,6tetrafluorobenzoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-])=O)#[N:2].O.O.[Sn](Cl)Cl.C(=O)(O)[O-:20].[Na+].O>C(O)C>[NH2:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:20]
Reactant: O=C([O-])O
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(N)=O)c(N)c1
Temperature: 25 °C

Procedure:
To a solution of 37.4 g (0.210 mol) of 4-cyano-3-nitroanisole in 500 mL of ethanol was added 221.6 g (0.982 mol) of tin(II) chloride dihydrate. The reaction mixture was stirred and heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was poured onto ice. Aqueous sodium bicarbonate was added slowly to the ice mixture until the solution reached pH 7-8. Additional water was added to the mixture, which was then extracted with methylene chloride (2×400 mL) and ethyl acetate (1×300 mL). The separated aqueous layers were filtered between each of the extractions. The off white residue collected on the filters was rinsed with methylene chloride and ethyl acetate several times. The combined organic phases were then dried over magnesium sulfate, filtered and evaporated in the rotary evaporator to obtain 28.5 g crude product (mp 154-155° C.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][CH:18]1[CH2:20][CH2:19]1)[C:9]([CH3:16])=[N:10]2)=[O:4].[C:21]([O:25][C:26]([NH:28][C@H:29]([CH3:38])[C:30](=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>[C:21]([O:25][C:26]([NH:28][CH:29]([CH3:38])[C:30](=[O:37])[CH:31]([CH2:2][C:3]([C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][CH:18]1[CH2:20][CH2:19]1)[C:9]([CH3:16])=[N:10]2)=[O:4])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:23])([CH3:24])[CH3:22]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1CC1
Reactant: CCOC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC3CC3)nc12)C(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of 2-bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (293c) (0.81 g, 2.38 mmol) and (R)-ethyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (0.74 g, 2.86 mmol) was dissolved in DMF (7.00 mL). Then K2CO3 (Acros Organics, New Jersey) (0.82 g, 5.95 mmol) was added into the reaction mixture. The overall mixture was stirred under inert atmosphere overnight. The mixture was diluted with saturated NaHCO3 (10 mL) and CHCl3 (20 mL). The layers were separated and the aq. layer was extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography through an Interchim PuriFlash UP (25 micron) pre-packed silica-gel column (40 gram), eluting with a gradient of 0-30% EtOAc in DCM, to provide ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (1.20 g, 2.32 mmol, 98% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([CH3:18])[CH:7]=[CH:8][CH2:9]P(OCC)(OCC)=O)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:30][C:31]1([CH3:49])[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[C:36]2[CH2:35][C:34]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])([CH:42]=O)[CH2:33][C:32]1=2.Cl>C1COCC1.CCCCCC>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([CH3:18])[CH:7]=[CH:8][CH:9]=[CH:42][C:34]1([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:33][C:32]2[C:31]([CH3:30])([CH3:49])[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[C:36]=2[CH2:35]1)[CH3:2]
Reactant: CCCCCC1(C=O)CC2=C(C1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C=C(C)C=CCP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC1(C=CC=CC(C)=CC(=O)OCC)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
680 mg of 6-(diethoxyphosphoryl)-3-methyl-hexa-2,4-dienoic acid ethyl ester were dissolved in 10 ml of THF and treated dropwise with 2.25 ml of a 1 molar solution of lithium bis(trimethylsilyl)amide in hexane at −78° C. After 10 minutes of stirring, a solution of 500 mg of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbaldehyde in 5 ml of THF was added dropwise at −78° C. The reaction mixture was slowly warmed to −40° C. and kept at this temperature for 3 hours. The cold reaction mixture was poured in ice/water, acidified with 1 N HCl and extracted with ether. The organic phase was washed with water, dried (Na2SO4) and the solvent was evaporated. The crude oil was purified with medium pressure chromatography (silica gel, hexane/tert.-butyl methyl ether 1%) to give 250 mg of pure (2Z, 4E, 6E)-3-methyl-7-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-hepta-2,4,6-trienoic acid ethyl ester and 400 mg of (2E, 4E, 6E)-3-methyl-7-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-hepta-2,4,6-trienoic acid ethyl ester as colorless oils.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:12])[C:8]=1[O:9][CH2:10][CH3:11])[NH2:5].[N:13]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>Cl.O.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:13])[CH:6]=[C:7]([CH3:12])[C:8]=1[O:9][CH2:10][CH3:11]
Reactant: O=N[O-]
Reactant: CCOc1c(C)cc(N)cc1C
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOc1c(C)cc(NN)cc1C
Yield: 93.6 %

Procedure:
To a cooled (+5° C.), stirred suspension of 9.2 g (0.0557 mol) of 3,5-dimethyl-4-ethoxyaniline in 50 ml of 6N HCl (aq), 3.8 g (0.0557 mol) of NaNO2 in 15 ml of water was added during 30 minutes. After stirring at +5° C. for 30 minutes further, the resulting mixture was added under argon and stirring to 29.1 g (0.167 mol) of sodium dithionite dissolved in 150 ml of water. After stirring for 20 minutes at +5° C., 250 ml of ether was added followed by alkalinization to pH 9 with 10N sodium hydroxide solution. The organic phase was separated and washed with sodium chloride solution. After drying (Na2SO4) the product was precipitated as the hydrochloride by addition of HCl(g)/ether (to pH 3). Filtration and washing with ether gave 9.4 g (78%) of the product.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([O:26][CH2:27]CBr)(=[O:25])[CH3:24]>>[CH3:27][O:26][C:23](=[O:25])[CH2:24][O:22][CH2:21][C@@H:19]1[CH2:18][S:17][C:16]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:20]1
Reactant: OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Reactant: CC(=O)OCCBr
Product: COC(=O)COC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1

Procedure:
[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-methanol prepared in Example 2 and bromoethyl acetate were reacted according to the same procedure as Step B of Preparation 29 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([C:19]1[CH:20]=[C:21]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[C:22]([O:36][CH3:37])=[C:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([OH:34])[CH:28]=2)[CH:24]=1)([CH3:18])([CH3:17])[CH3:16]>C(#N)C.CN(C)C=O.O>[C:15]([C:19]1[CH:20]=[C:21]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[C:22]([O:36][CH3:37])=[C:23]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([O:34][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:28]=2)[CH:24]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(O)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2ccc(C)c(Oc3ccnc(Cl)n3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
567 mg 2,4-dichloropyrimidine and 663 mg potassium carbonate are added to 1.50 g N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-3-hydroxy-4-methyl-benzamide in 15 ml acetonitrile and 3 ml N,N-dimethylformamide, and the reaction mixture is stirred overnight at ambient temperature. Then another 57 mg 2,4-dichloropyrimidine are added, and the mixture is stirred for a further hour at ambient temperature. For working up the reaction mixture is diluted with water and the white precipitate formed is filtered off, washed with water and dried in the desiccator.