Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:10][O:11][C:12]1[C:17]2[NH:18]C(=O)[O:20][C:21](=O)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C[Al](C)C.Cl>C1(C)C=CC=CC=1>[NH2:18][C:17]1[C:12]([O:11][CH3:10])=[CH:13][CH:14]=[CH:15][C:16]=1[C:21]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[C:3]=1[CH3:9])=[O:20]
Reactant: COc1cccc2c(=O)oc(=O)[nH]c12
Reactant: Cc1c(N)cccc1Br
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
A mixture of 3-bromo-2-methylaniline (482 mg, 2.59 mmol) and 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (500 mg, 2.59 mmol) in toluene (20 mL) was treated with 2 M trimethylaluminum in toluene (3.24 mL, 6.47 mmol) at 0° C. The mixture was stirred at room temperature for 10 minutes, then was heated at 70° C. overnight. The mixture was cooled to room temperature, treated with 1N aqueous HCl and extracted 3 times with EtOAc. The combined organic phases were washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated. The residue was subjected to column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide 2-amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide as a white solid (302 mg, 35% yield). Mass spectrum m/z 335, 337 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.72 (d, J=7.3 Hz, 2H), 7.46 (dd, J=8.0, 0.8 Hz, 1H), 7.17-7.10 (m, 2H), 6.90 (dd, J=7.9, 0.9 Hz, 1H), 6.72-6.66 (m, 1H), 5.88 (br. s., 2H), 3.92 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>C(O)(C)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Cl)c(-c2cccnc2)c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(Nc1ccc(Cl)c(-c2cccnc2)c1)Oc1ccccc1
Temperature: -40 °C
Yield: 94.7 %

Procedure:
4-Chloro-3-(pyrid-3-yl)aniline (0.08 g, 0.00039 mole) in isopropyl alcohol (8 ml) was cooled to -40° C. and treated under argon with triethylamine (0.06 ml, 0.00043 mole) followed dropwise by phenyl chloroformate (0.051 ml, 0.00041 mole). The reaction mixture was stirred at -40° C. for half an hour and allowed to warm to ambient temperature. The solvent was removed in vacuo and the residue dissolved in dichloromethane, washed with HO, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.12 g, 95%) as an orange solid.
Reaction SMILES: [C:1]([C@H:4]([NH:6][C:7]([C@@H:9]([NH:11][C:12]([C:14]1[N:18]2[C@@:19]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=3)([CH3:31])[C:20](=[O:30])[N:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:17]2=[N:16][CH:15]=1)=[O:13])[CH3:10])=[O:8])[CH3:5])(=[S:3])[NH2:2].[CH2:41](OC(OCC)CBr)[CH3:42].Cl>CC(C)=O.O1CCOCC1>[S:3]1[CH:42]=[CH:41][N:2]=[C:1]1[CH:4]([NH:6][C:7]([C@@H:9]([NH:11][C:12]([C:14]1[N:18]2[C@@:19]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]#[N:40])=[CH:37][CH:38]=3)([CH3:31])[C:20](=[O:30])[N:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:17]2=[N:16][CH:15]=1)=[O:13])[CH3:10])=[O:8])[CH3:5]
Reactant: CCOC(CBr)OCC
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N[C@H](C)C(N)=S
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(NC(=O)[C@H](C)NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)c1nccs1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [(S)-1-((R)-1-thiocarbamoyl-ethylcarbamoyl)-ethyl]-amide (132 mg, 0.22 mmol) in 1 mL of acetone was added bromoacetaldehyde diethyl acetal (0.166 mL, 1.10 mmol) and HCl in dioxane (4 M, 0.003 mL, 0.01 mmol). The reaction mixture was heated at reflux for 5 h, and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 25 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The organic phase was washed with water and brine (10 mL each), dried over Na2SO4, filtered, and concentrated in vacuo to a pale brown oil. The crude product was purified by flash chromatography on silica gel, eluting with 0-5% MeOH in CH2Cl2, to furnish 122 mg (89%) of the title compound as a pale brown foam, obtained as a 1:1 mixture of thiazole α-methyl diastereomers, m/z 622.3 [M+1]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])[CH3:10]>>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:9](=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)c1ccc2ccccc2c1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 2-acetylnaphthalene, 1-(2-naphthalenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]>>[NH2:1][C:2]1[C:7]([O:8][CH2:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1O
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(COc2cc(Cl)cnc2N)c1

Procedure:
The title compound was prepared using the method of Preparation 22 from 2-amino-5-chloro-3-pyridinol and methyl 3-(bromomethyl)benzoate to give a tan solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:11][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 102 %

Procedure:
A mixture of 1-(o-methoxyphenyl)piperazine (0.19 mol), N-(3-bromopropyl)phthalimide (0.186 mol) and micropulverized potassium carbonate (0.465 mol) in acetonitrile (375 ml) was heated at reflux for 16 hours. The cooled mixture was evaporated in vacuo and the residue diluted with water (800 ml) and extracted with chloroform (4×350 ml). After drying (MgSO4), the combined extracts were evaporated in vacuo. The residue was dried under high vacuum (<0.05 mm of Hg) at room temperature for 16 hours resulting in 72.0 g of a yellow solid ~100% yield); mp 85°-93° C. Spectral data were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH2:28][CH2:27][CH2:26][C:25]=2Br)[N:19]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH2:28][CH2:27][CH2:26][C:25]=2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])[N:19]=1)=[O:17])[CH3:14]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)n1
Product: CCOC(=O)c1cccc(C2=C(c3cc(F)ccc3OC)CCC2)n1

Procedure:
Prepared by general procedure B(iii) but using 5-fluoro-2-methoxyphenylboronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid and 6-(2-bromocyclopent-1-enyl)-pyridine-2-carboxylic acid ethyl ester instead of 3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[Cl:9][C:10]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15](Cl)=[O:16].[OH-].[Na+]>O.ClC(Cl)Cl>[Cl:9][C:10]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15]([N:1]1[CH2:3][CH2:2]1)=[O:16]
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)Cl
Reactant: C1CN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)N1CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To 230 parts of a solution of aziridine in water 0.875M are added 15 parts of sodium hydrogen carbonate while cooling at 0° C. Then there is added dropwise, during a 45 minutes-period, a solution of 42.5 parts of 5-chloro-2-methoxy-4-nitrobenzoyl chloride in 150 parts of trichloromethane at 0° C and while stirring vigorously. The mixture is diluted with about 150 parts of trichloromethane and the whole is stirred for 45 minutes without cooling. The reaction mixture is alkalized to pH 8 with a diluted sodium hydroxide solution. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated, yielding 40 parts of 1-(5-chloro-2-methoxy-4-nitrobenzoyl)aziridine.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C=O)C>[CH2:23]([O:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(=O)c1cc(OCCCCCCCCCCCCCCCCCCCCCC)ccc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
2,7-Dihydroxy-9-fluorenone (1 g, 4.71 mmol) was dissolved in DMF (40 ml), and potassium carbonate (1.95 g, 14.1 mmol) and docosyl bromide (96%, 4.02 g, 9.91 mmol) were added. The mixture was stirred overnight at 80° C., docosyl bromide (0.40 g, 0.99 mmol) was further added and the mixture was stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, 1N hydrochloric acid (120 ml) was added thereto in a water bath to allow precipitation. The crystals were collected by filtration and slurry washed once with 1N hydrochloric acid (40 ml), once with pure water (40 ml) and once with methanol (40 ml) to give 2,7-didocosyloxy-9-fluorenone (4.20 g, docosyl bromide mixture).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 2-aminophenol (1.09 g, 10.0 mmol) and triethylamine (2.09 mL, 15.0 mmol) in THF (20 mL) was added benzoyl chloride (1.16 mL, 10.0 mmol) in THF (4 mL) dropwise over a period of 5 min at 0° C. After addition was complete the reaction mixture was kept on stirring at room temperature for overnight. The reaction mixture was concentrated at reduced pressure. The residue was taken up in methanol, aqueous sodium hydroxide (NaOH) (8M, 5 mL) was added. After 5 min the pH of the reaction mixture was adjusted to 7.0 by addition of glacial acetic acid and concentrated in vacuo. The reaction mixture was dissolved in dichloromethane (CH2Cl2), washed successively with 1M aqueous hydrochloric acid (HCl), saturated aqueous sodium hydrogen carbonate (NaHCO3). The organic layer was dried over sodium sulphate (Na2SO4), filtered and concentrated to give desired product (1.69 g).
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22]C2C=CC=CC=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][O:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][O:36]2)=[O:34])[C@@:17]([NH:20][C:21](=[O:29])[CH3:22])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Reactant: O=C(CBr)C1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@](NC(C)=O)(c3ccccc3)[C@H]2SCC(=O)C2CCCO2)cc1
Reaction time: 0.17 h

Procedure:
The crude thiol was dissolved in acetone (35 ml) and treated with a solution of (RS)-2-bromoacetyltetrahydrofuran (3.48 g, 18.0 mmol) in acetone (5 ml). After 10 min, potassium carbonate (1.24 g, 8.9 mmol) was added, and the mixture stirred for a further 30min. The reaction mixture was diluted with ethyl acetate, washed successively with water (x2) and brine, dried and concentrated. The residue was flash chromatographed on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane yielding the title compound as a colourless foam (5.40 g, 55%); νmax (CH2Cl2) 3409, 1781, 1745, 1684, 1613, 1516 cm-1. [Mass spectrum +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (565)].
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])=[CH:5][CH:4]=1.[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([Cl:34])[CH:26]=1)=[S:23])[NH2:21]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:21][NH:20][C:22]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([Cl:34])[CH:26]=3)=[S:23])[CH3:17])[C:13]=2[OH:14])=[CH:5][CH:4]=1
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1)c1csc(-c2ccc(C(F)(F)F)cc2)c1O

Procedure:
From 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonylthiophene (50.0 mg, 0.17 mmol) and 4-hydrazinocabonothioylamino-2-chlorobenzoic acid (42.9 mg, 0.17 mmol), the desired product was obtained in the same manner as in Synthetic Example 118 as a pale yellow solid (58.3 mg, yield 65%).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][C:34]([F:43])([F:42])[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:38][CH2:37][N:36]([CH2:35][C:34]([F:42])([F:43])[F:33])[CH2:41][CH2:40]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: FC(F)(F)CN1CCNCC1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCN(CC(F)(F)F)CC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-(2,2,2-trifluoroethyl)piperazine to afford an off-white powder. HPLC (Condition 4) tR=6.3 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=531 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.59-2.70 (m, 4H) 3.08-3.26 (m, 6H) 6.59-6.73 (m, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.86 (d, J=9.38 Hz, 3H) 8.27-8.37 (m, 1H) 8.73 (s, 1H) 10.40 (br. s, 1H) 13.02-13.18 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH2:20][CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[OH:25][CH2:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH2:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[N:32][C:27]([CH2:26][OH:25])=[CH:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:24])[C:13]2=[O:23])[C:16]([CH3:22])=[N:17]1)[CH3:21]
Reactant: OCc1ccc(B(O)O)cn1
Reactant: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: CCn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5ccc(CO)nc5)cc4c32)c(C)n1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 80 mg, 0.207 mmol) and 6-(hydroxymethyl)pyridine-3-boronic acid (Combi-Blocks, San Diego, USA, 39 mg, 0.254 mmol) to give the title compound as a white solid. (HPLC: tR 2.04 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.61-8.56 (m, 1H), 8.21-8.17 (m, 1H), 8.15-8.09 (m, 1H), 7.97-7.93 (m, 1H), 7.90-7.85 (m, 1H), 7.57-7.49 (m, 2H), 5.47 (t, 1H), 4.61-4.55 (m, 2H), 4.23-4.14 (m, 2H), 3.57 (s, 3H), 1.95 (s, 3H), 1.43 (t, 3H))
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH2:5][CH2:6][O:7][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: COC(=O)C(CCO)Oc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CCOS(=O)(=O)c1ccc(C)cc1)Oc1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
To a solution of 2-(4-Chloro-phenoxy)-4-hydroxy-butyric acid methyl ester (Example 473b), 0.225 g) in dichloromethane (1.88 mL) at room temperature, was added triethylamine (116 mg) and 4-methylbenzene-1-sulfonyl chloride (177 mg). The mixture was stirred at 22° C. for 48 hr. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (169 mg; 46%). MS (ESI): m/z=419 [M+NH4]+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[C:14]([CH3:29])([CH3:28])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:29][C:14]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH3:28]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(Br)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
In 75 ml of dry N,N-dimethylformamide are dissolved 14.7 g of N-hydroxyphthalimide and 27.2 g of p-nitrobenzyl α-bromoisobutyrate, followed by addition of 12.4 g of potassium carbonate. The mixture is stirred at room temperature for one hour. The stirring becomes difficult due to precipitation of an orange-colored solid and, therefore, 75 ml of dry N,N-dimethylformamide is added. After 24 hours of stirring at room temperature, the reaction mixture is concentrated under reduced pressure to about half its original volume and the concentrate is put in 700 ml of water with ice-cooling and stirring. The mixture is further stirred for 30 minutes and the resultant crystalline precipitate is recovered by filtration and washed with water. The crystals are dissolved in 500 ml of methylene chloride, washed with water and dried over anhydrous magnesium sulfate. The sulfate is then distilled off under reduced pressure. The solid residue is washed with ether-petroleum ether (1:1) and a small amount of ether in this order to give 27.0 g of N-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxy]phthalimide as colorless crystals, m.p. 145°-146° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7][C:6]1=[O:22])[CH3:4].[CH3:23][O:24][C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CN(C=O)C>[CH3:23][O:24][C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:5]([CH2:3][CH3:4])[C:6]1=[O:22]
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: CCn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(-c2ccccc2)c(-c2ccccc2)n(CCCCCCCCCCC(=O)OC)c1=O

Procedure:
The product is produced as described in example 1 from 0.45 g of NaH (80% suspension in mineral oil), 4 g of 1-ethyl-4.5-diphenyl-4-imidazolin-2-one, 30 cc. of DMF, 4.2 g of 11-bromoundecanoic acid methyl ester and 0.45 g of NaJ.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9][CH2:8]1)C.[OH-].[Na+].C(O)C>O>[CH2:22]([O:21][C:5](=[CH:6][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH2:10][CH2:9][CH2:8]1)[C:4]([OH:24])=[O:3])[CH3:23]
Reactant: CCOC(=O)C(=CC1(c2ccccc2C(F)(F)F)CCC1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
4.6 g of 2-Ethoxy-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-acrylic acid ethyl ester, 4.3 g of sodium hydroxide, 100 ml ethanol and 50 ml water (ethanol-water 2:1) were mixed and stirred for 2 hours at room temperature. Solvent was evaporated in vacuum, residue was distributed between water and ethyl acetate, and water solution was acidified with IN hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extracts were washed with saturated aqueous sodium chloride solution, dried and concentrated by evaporation in a vacuum. 4.3 g of product was obtained and used for the next reaction without further purification.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>CN(C)C=O.O>[CH3:15][N:16]([CH3:20])[C:17]([NH:1]/[C:2](/[C:9]([F:10])([F:11])[F:12])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(\NC(=O)N(C)C)C(F)(F)F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
Ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100 mmol) is added to a stirred solution of sodium hydride (60% in mineral oil, 9.6 g, 250 mmol) in N,N-dimethyl-formamide (60 mL) at 5° C. under nitrogen over a 60 minute period. The reaction mixture is allowed to warm to and held at room temperature for 15 minutes, cooled to 5° C., and treated with dimethylcarbamoylchloride (21.6 g, 200 mmol) over a 60 minute period. The resultant solution is then warmed to and held at room temperature for 2 hours, diluted with water (150 mL), and extracted with ethyl acetate (2×150 mL). The combined organic layers are dried, filtered and concentrated, and the mineral oil layer is removed to obtain a residue. Flash column chromatography of the residue on silica gel using a 85:15 hexanes/ethyl acetate solution gives the title product as a yellow liquid (18.1 g, 71% yield): 1H NMR (DMSO-d6)δ 9.18 (s,1H), 5.85 (s, 1H), 4.20 (q, 2H), 2.89 (s, 6H), 1.18 (t, 3H) ; 19F NMR δ −65.7 (s).